IntroductionAcute graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality after allogeneic bone marrow transplantation (BMT) and occurs as a result of the activation, proliferation, and effector cell function of donor T cells that, along with the release of proinflammatory cytokines, result in tissue damage. 1 Recently, a subset of CD4 ϩ T cells with potent suppressor activity, CD4 ϩ 25 ϩ regulatory T cells (Tregs), 2 have been shown to inhibit alloreactive T-cell activation and effector cell function 3,4 and GVHD lethality in murine models. [5][6][7] Thus, Tregs are attractive therapeutic tools for preventing GVHD in humans. [8][9][10][11] When administered at the time of BMT, typically Tregs must be given at approximately the same number of donor T cells (1:1 ratio) to be highly effective at preventing GVHD. [5][6][7] This poses a technical problem since Tregs are present in low frequency in the peripheral blood (ϳ 1% are CD4 ϩ CD25 br cells) 12 and contaminating CD4 ϩ 25 Ϫ T cells out-compete Tregs for expansion and result in loss of Treg suppressor cell function. 11,13 Therefore, many laboratories have been dedicated to developing new approaches for the isolation and expansion of human Tregs from adult peripheral blood without loss of suppressor cell function.Tregs express multiple tumor necrosis factor receptor (TNFR) family members on their cell surface, including glucocorticoidinduced tumor necrosis factor receptor (GITR), OX40 (CD134), and 4-1BB (CD137). 14,15 While it is generally accepted that TNFR expressed on naive T cell functions contributes to T-cell survival (reviewed in Watts 16 ), the exact role of TNFR signaling in Treg generation, expansion, and suppression is unclear. Shimizu and coworkers have shown that stimulation of GITR abrogates Treg suppressor function, 17 although in other studies, McHugh et al showed that loss of suppression depends on whether or not TCR triggering and IL-2 are present before GITR engagement. 15 We have shown that blockade of CD40L signaling on Tregs increases their suppressive function and tolerogenic capacity. [18][19][20] Since signaling via CD40L and GITR can reduce suppressor cell function, neither would seem advantageous for human Treg expansion cultures, so we focused on OX40 and 4-1BB. While OX40 signals do not appear to increase in vitro anti-CD3 mAb/ APC-driven Treg proliferation, 21-23 a recent report indicates that OX40 signals can increase endogenous Treg survival in vivo, 24 although other studies indicated that OX40 signals provided during ex vivo Treg expansion inhibited rodent Treg suppressor function and foxP3 expression. 21,22,24 In humans, OX40L-mediated signaling has been reported to inhibit the generation of IL-10-producing T-regulatory type 1 cells from naive and memory CD4 ϩ T cells and to shut down both IL-10 production and suppressor cell function. 25 4-1BB also is expressed on resting Tregs and up-regulated within 2 days after in vitro anti-CD3 mAb plus IL-2 stimulation. 26 In vitro anti-CD3 mAb or antigen-induce...

PURPOSE To improve the outcomes of patients with T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LL), the proteasome inhibitor bortezomib was examined in the Children's Oncology Group phase III clinical trial AALL1231, which also attempted to reduce the use of prophylactic cranial radiation (CRT) in newly diagnosed T-ALL. PATIENTS AND METHODS Children and young adults with T-ALL/T-LL were randomly assigned to a modified augmented Berlin-Frankfurt-Münster chemotherapy regimen with/without bortezomib during induction and delayed intensification. Multiple modifications were made to the augmented Berlin-Frankfurt-Münster backbone used in the predecessor trial, AALL0434, including using dexamethasone instead of prednisone and adding two extra doses of pegaspargase in an attempt to eliminate CRT in most patients. RESULTS AALL1231 accrued 824 eligible and evaluable patients from 2014 to 2017. The 4-year event-free survival (EFS) and overall survival (OS) for arm A (no bortezomib) versus arm B (bortezomib) were 80.1% ± 2.3% versus 83.8% ± 2.1% (EFS, P = .131) and 85.7% ± 2.0% versus 88.3% ± 1.8% (OS, P = .085). Patients with T-LL had improved EFS and OS with bortezomib: 4-year EFS (76.5% ± 5.1% v 86.4% ± 4.0%; P = .041); and 4-year OS (78.3% ± 4.9% v 89.5% ± 3.6%; P = .009). No excess toxicity was seen with bortezomib. In AALL0434, 90.8% of patients with T-ALL received CRT. In AALL1231, 9.5% of patients were scheduled to receive CRT. Evaluation of comparable AALL0434 patients who received CRT and AALL1231 patients who did not receive CRT demonstrated no statistical differences in EFS ( P = .412) and OS ( P = .600). CONCLUSION Patients with T-LL had significantly improved EFS and OS with bortezomib on the AALL1231 backbone. Systemic therapy intensification allowed elimination of CRT in more than 90% of patients with T-ALL without excess relapse.

Risk-adapted, response-based therapies for pediatric Hodgkin lymphoma have resulted in 5-year survival exceeding 90%. Although high-dose chemotherapy and autologous hematopoietic stem cell transplantation (AHSCT) are considered standard for most patients with relapsed or refractory Hodgkin lymphoma, a subset of children with low risk relapse do not require AHSCT for cure. Currently there are no widely accepted criteria defining who should receive standard dose chemotherapy and/or radiotherapy, nor is there a standardized treatment regimen. We propose a risk-stratified, response-based algorithm for children with relapsed or refractory Hodgkin lymphoma that is based on a critical appraisal of published outcomes and prognostic factors.

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Opportunistic infections contribute to morbidity and mortality of patients undergoing hematopoietic stem cell transplantation and treatment for malignancies. Rothia mucilaginosa, a gram-positive bacterium, is responsible for rare, but often fatal meningitis in severely immunocompromised patients. We describe two cases of meningitis from discrete strains of R. mucilaginosa on our pediatric bone marrow transplant unit, summarize the published cases of R. mucilaginosa meningitis in oncology and stem cell transplant patients, and provide updated recommendations regarding the use of antibiotic therapy in this patient population.