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Background: Relapse remains a challenge after transplantation in pediatric patients with hematological malignancies. Myeloablative regimens used for disease control are associated with acute and long-term adverse effects. We used a CD45RA-depleted haploidentical graft for adoptive transfer of memory T cells combined with NK-cell addback and hypothesized that maximizing the graft-versus-leukemia (GVL) effect might allow for reduction in intensity of conditioning regimen., Methods: In this phase II clinical trial (NCT01807611), 72 patients with hematological malignancies (complete remission (CR)1: 25, ≥ CR2: 28, refractory disease: 19) received haploidentical CD34 + enriched and CD45RA-depleted hematopoietic progenitor cell grafts followed by NK-cell infusion. Conditioning included fludarabine, thiotepa, melphalan, cyclophosphamide, total lymphoid irradiation, and graft-versus-host disease (GVHD) prophylaxis consisted of a short-course sirolimus or mycophenolate mofetil without serotherapy., Results: The 3-year overall survival (OS) and event-free-survival (EFS) for patients in CR1 were 92% (95% CI:72-98) and 88% (95% CI: 67-96); ≥ CR2 were 81% (95% CI: 61-92) and 68% (95% CI: 47-82) and refractory disease were 32% (95% CI: 11-54) and 20% (95% CI: 6-40). The 3-year EFS for all patients in morphological CR was 77% (95% CI: 64-87) with no difference amongst recipients with or without minimal residual disease (P = 0.2992). Immune reconstitution was rapid, with mean CD3 and CD4 T-cell counts of 410/μL and 140/μL at day + 30. Cumulative incidence of acute GVHD and chronic GVHD was 36% and 26% but most patients with acute GVHD recovered rapidly with therapy. Lower rates of grade III-IV acute GVHD were observed with NK-cell alloreactive donors (P = 0.004), and higher rates of moderate/severe chronic GVHD occurred with maternal donors (P = 0.035)., Conclusion: The combination of a CD45RA-depleted graft and NK-cell addback led to robust immune reconstitution maximizing the GVL effect and allowed for use of a submyeloablative, TBI-free conditioning regimen that was associated with excellent EFS resulting in promising long-term outcomes in this high-risk population. The trial is registered at ClinicalTrials.gov (NCT01807611)., (© 2024. The Author(s).)

Patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (HCT) have a poor prognosis. Although proceeding to subsequent HCT can provide potential for long-term survival, there are limited data to guide which patients are most likely to benefit and which HCT strategies are best in this heavily pretreated population. The goals of this study were to describe the clinical outcomes of subsequent HCT in pediatric patients with relapsed hematologic malignancies in a cohort enriched for haploidentical donors, and to evaluate the associations of patient-, disease-, and treatment-related factors with survival. We retrospectively evaluated patients who underwent a subsequent HCT for management of post-HCT relapse at a single institution between 2000 and 2021. Among 106 patients who underwent a second allogeneic HCT, the 1-year event-free survival (EFS) was 34% and 1-year overall survival (OS) was 46%, with a 5-year EFS of 26% and 5-year OS of 31%. Only disease-related factors were associated with outcome after second HCT-specifically, the interval between HCTs and the presence or absence of active disease at the time of HCT. In this cohort, patient- and treatment-related factors were not associated with differences in EFS or OS. Patients undergoing a third or fourth HCT (n = 13) had comparable survival outcomes to those undergoing a second HCT. Our experience highlights that a subsequent HCT has curative potential for a subset of patients who relapse after HCT, including those who undergo a subsequent HCT from a haploidentical donor. Although relapse and treatment-related toxicities remain major challenges, our study indicates that achieving complete remission prior to subsequent HCTs has the potential to further improve outcomes., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Pediatric patients with high-risk hematologic malignancies who experience relapse after a prior allogeneic hematopoietic cell transplant (HCT) have an exceedingly poor prognosis. A second allogeneic HCT offers the potential for long-term cure but carries high risks of both subsequent relapse and HCT-related morbidity and mortality. Using haploidentical donors for HCT (haploHCT) can expand the donor pool and potentially enhance the graft-versus-leukemia effect but is accompanied by a risk of graft-versus-host disease (GVHD). The goal of this protocol was to intensify the antileukemia effect of haploHCT for pediatric patients with hematologic malignancies that relapsed after prior allogeneic HCT, while limiting regimen-associated toxicities. This phase II clinical trial evaluated a sub-myeloablative preparative regimen consisting of anti-thymocyte globulin, clofarabine, cytarabine, busulfan, and cyclophosphamide, in combination with plerixafor to sensitize leukemic blasts. Participants received a mobilized peripheral blood unmanipulated haploidentical donor graft with one dose of post-transplant cyclophosphamide as GVHD prophylaxis, followed by natural killer (NK) cell addback. Here we report the clinical outcomes and immune reconstitution of 17 participants treated on the study and 5 additional patients treated on similar single-patient treatment plans. Of the 22 participants analyzed, 12 (55%) had active disease at the time of HCT. The regimen provided robust immune reconstitution, with 21 participants (95%) experiencing neutrophil engraftment at a median of 14 days after HCT. In this high-risk population, the overall survival was 45% (95% confidence interval [CI], 24%-64%), with a 12-month event-free survival of 31% (95% CI, 14%-51%) and cumulative incidence of relapse at 12 months of 50% (95% CI, 27%-69%). Four participants (18%) remain in remission at >5 years follow-up. Expected HCT-related organ-specific toxicities were observed, and 13 participants (59%) experienced acute or chronic GVHD. This intensified but sub-myeloablative regimen, followed by a high-dose unmanipulated haploidentical graft, post-transplantation cyclophosphamide, and NK cell infusion, resulted in adequate immune reconstitution but failed to overcome the elevated risks of relapse and treatment-related morbidity in this high-risk population., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Disease relapse remains a major cause of treatment failure in patients receiving allogeneic hematopoietic cell transplantation (alloHCT) for high-risk acute leukemias or myelodysplastic syndromes (MDS). Comprehensive data on outcomes after post-transplant relapse are lacking, especially in pediatric patients. Our objective was to assess the impact of various transplant-, patient-, and disease-related variables on survival and outcomes in patients who relapse after alloHCT. We describe our institutional experience with 221 pediatric patients who experienced disease relapse after their first alloHCT for acute leukemias or MDS between 1990 and 2018. In a multivariable model, being in first complete remission at first alloHCT, longer duration of remission after alloHCT, experiencing GVHD and receiving a transplant in a more recent time period were significantly associated with a higher likelihood of receiving a second alloHCT after post-transplant relapse. Of these variables, only longer interval from alloHCT to relapse, receiving a second alloHCT or DLI, and receiving a transplant in a more recent time period were associated with improved overall survival. Our data support pursuing second alloHCT for patients who have experienced relapse after their first transplant, as that remains the only salvage modality with a reasonable chance of inducing long-term remission., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: Bacteremia is a leading cause of morbidity and mortality in children undergoing hematopoietic cell transplantation (HCT). Infections of vancomycin-resistant enterococci (VRE) and multidrug resistant (MDR) gram-negative rods (GNRs) are common in this population. Our objective was to assess whether experimental bath wipes containing silver were more effective than standard bath wipes containing soap at reducing skin colonization by VRE and MDR GNRs, and nonmucosal barrier injury bacteremia. Study Design: Patients undergoing autologous or allogeneic HCT in a tertiary referral center were randomized to receive experimental or standard bath wipes for 60 days post-HCT. Skin swabs were collected at baseline, discharge, and day +60 post-HCT. The rate of VRE colonization was chosen as the marker for efficacy. Results: Experimental bath wipes were well tolerated. Before the study, the rate of colonization with VRE in HCT recipients was 25%. In an interim analysis of 127 children, one (2%) patient in the experimental arm and two (3%) in the standard arm were colonized with VRE. Two (3%) patients had nonmucosal barrier injury bacteremia in the standard arm, with none in the experimental arm. MDR GNRs were not isolated. The trial was halted because the interim analyses indicated equivalent efficacy of the two methods. Conclusions: Skin cleansing with silver-containing or standard bath wipes resulted in very low and equivalent rates of bacteremia and colonization with VRE and MDR GNRs in children post-HCT. Future studies in other high-risk populations are needed to confirm these results.

T-cell depletion of an HLA-haploidentical (haplo) graft is often used to reduce the risk of graft-versus-host disease (GVHD), but the lack of donor T cells in the infused product may lead to graft failure, slow T-cell reconstitution, infections, and relapse. More selective T-cell depletion targeting CD45RA can effectively deplete naive T cells but preserve large numbers of memory T cells leading to robust engraftment of diverse T-cell populations and reduction of viremia in the early posttransplant period. Herein, we report the outcome of 143 pediatric and young adult hematologic malignancy patients receiving a first allogeneic hematopoietic cell transplantation (HCT) on six consecutive ex vivo T-cell depleted haploHCT protocols over the past 15 years at a single institution-including the first 50 patients on an active CD45RA-depleted haploHCT study in which patients also received NK-cells and pharmacological GvHD prophylaxis post transplant. Our data demonstrated an increase in the 3-year overall survival and event-free survival in nonchemorefractory recipients receiving CD45RA-depleted grafts (78.9% and 77.7%, respectively) compared with historic T-cell depleted haploHCT cohorts (46.7% and 42.7%, respectively, p = 0.004, and 0.003). This improvement was primarily due to a reduction in transplant related mortality without significant increase in the rates of GVHD.

The current approach for preventing hemolysis of red blood cells (RBCs) in major ABO-incompatible bone marrow (BM) grafts after infusion is to deplete RBCs from BM products before transplantation. Traditionally, manual density separation (MDS) using Ficoll-Hypaque (Cytiva Sweden AB, Uppsala, Sweden has been used to accomplish RBC depletion. This process yields good CD34+ cell recovery, but it requires open manipulation and is labor-intensive and time-consuming. We hypothesized that an alternative automated method using Haemonetics Cell Saver 5+ (Haemonetics Corporation, Boston, MA, USA) would offer equivalent RBC depletion and CD34+ cell recovery. Small marrow volumes from pediatric donors can be processed using Cell Saver (CS) without adding the third-party RBCs necessary for other automated methods. This retrospective analysis comprised data from 58 allogeneic BM grafts. RBC depletion and CD34+ cell recovery from BM using MDS (35 grafts) were compared with CS (14 grafts). Nine products underwent RBC depletion using CS with Ficoll (CS-F) when RBC volume was less than 125 mL. Linear regression analysis of log transformation of CD34+ cell recovery adjusted for log transformation of both baseline CD34+ cell content and baseline total volume showed no significant difference between MDS and CS (estimated coefficient, –0.121, P = 0.096). All products contained an RBC volume of less than 0.25 mL/kg post-processing. CD34+ cell recovery with CS-F was comparable to MDS and CS and suitable for pediatric recipients of allogeneic hematopoietic cell transplantation. We provide evidence that an automated method using Haemonetics Cell Saver 5+ achieves RBC depletion and CD34+ cell recovery comparable to MDS when adjusting for baseline factors. [ABSTRACT FROM AUTHOR]

Pulmonary complications are common in children following hematopoietic cell transplantation (HCT) and contribute to their morbidity and mortality. Early diagnosis is essential for management and prevention of progression of lung injury and damage. In many cases, diagnosis can be challenging and may require diagnostic imaging and more invasive testing such as bronchoscopy and lung biopsy. We report the case of a 12-year-old girl who developed recurrent episodes of acute respiratory failure requiring intensive care unit admission in the post-HCT phase and describe the diagnostic and multidisciplinary approach for her management. In addition, we review the diagnostic approach of pulmonary complications post-HCT and highlight the utility and risks of bronchoscopy and lung biopsy in these children. [ABSTRACT FROM AUTHOR]