Andromachi Scaradavou

Double-unit cord blood transplantation (dCBT) has been associated with high rates of progression-free survival (PFS) in adults with hematologic malignancies but also with relatively high rates of acute graft-versus-host disease (aGVHD). We conducted a single-arm, phase 2 clinical trial that investigated the addition of tocilizumab, an interleukin-6 receptor blocker, to cyclosporine-A (CSA) and mycophenolate mofetil (MMF) for aGVHD prophylaxis after intermediate-intensity dCBT. A total of 45 patients (median age, 47 years; range, 27-60 years; 80% acute leukemia; median hematopoietic cell transplant-comorbidity index, 2) were enrolled from March 2018 to March 2021. Transplant outcomes were compared with 39 previous CSA and MMF dCBT controls with similar inclusion criteria. Tocilizumab recipients had less pre-engraftment syndrome (38%; 95% confidence interval [CI], 24-52 vs 72%; 95% CI, 54-84; P < .001) but inferior day 45 neutrophil engraftment (93%; median, 25.5 days vs 97%; median, 22 days; P = .009]. The primary end point of day 100 grade 2 to 4 aGVHD was no different between groups (71%; 95% CI, 55-82 with tocilizumab vs 82%; 95% CI, 65-91; P = .11). However, there was a trend toward a lower day 100 incidence of stage 1 to 4 lower gastrointestinal aGVHD with tocilizumab (16%; 95% CI, 7-28 vs 33%; 95% CI, 19-48; P = .059). There were no significant differences in the 3-year incidences of relapse, transplant-related mortality, PFS, or overall survival between the groups. Tocilizumab recipients exhibited a distinct pattern of gut microbiome disruption. In summary, tocilizumab-based GVHD prophylaxis delayed neutrophil recovery without a significant reduction in aGVHD and had no survival benefit after dCBT. Investigation of alternative strategies to prevent severe aGVHD after dCBT is warranted. This trial was registered at www.clinicaltrials.gov as #NCT03434730.

Antithymocyte globulin (ATG) is used in pediatric allogeneic hematopoietic cell transplantation (HCT) to prevent graft-versus-host disease (GVHD) and graft failure (GF). Poor T-cell recovery, associated with increased mortality, is the main toxicity of ATG. Model-based precision dosing of ATG (MBD-ATG) minimizes toxicity while maintaining efficacy. We report updated results of the single-arm phase 2 PARACHUTE trial investigating MBD-ATG, combined with real-world experience using identical MBD-ATG. Consecutive patients receiving a first T-cell–replete HCT for any indication were evaluated. Results were compared with historical patients receiving conventional fixed ATG dosing (FIX-ATG). Primary outcome was overall survival (OS). The MBD-ATG group consisted of 214 patients (58 trial patients; 156 real-world patients); 100 patients received FIX-ATG. MBD-ATG led to superior OS compared with FIX-ATG (hazard ratio [HR] for death, 0.56; 95% confidence interval [CI], 0.34-0.93; P = .026), and lower treatment-related mortality (TRM; HR, 0.51; 95% CI, 0.29-0.92; P = .025). Successful T-cell reconstitution (>0.05 × 109/L CD4+ T cells twice within 100 after HCT) was improved in MBD-ATG vs FIX-ATG (87% ± 2% vs 47% ± 5%; P < .0001). The improved T-cell reconstitution led to lower TRM (HR, 0.19; 95% CI, 0.09-0.36; P < .0001). Incidence of grade 2-4 acute GVHD was comparable, whereas chronic GVHD (HR, 0.35; 95% CI, 0.17-0.72; P = .004) and GF (HR, 0.36; 95% CI, 0.13-0.97; P = .044) were both less frequent in MBD-ATG compared with FIX-ATG. MBD-ATG results in improved OS and reduced TRM, while reducing chronic GVHD and GF. This easy-to-implement approach improves outcomes after pediatric HCT, confirmatory studies are needed. The PARACHUTE trial is registered with the Dutch Trial Register as #NL4836.

Frozen/stored cord blood (CB) products are available for clinical use without delays, facilitating timely transplantation for patients who need urgent treatment, such as those with acute leukaemia. Given the less strict Human Leukocyte Antigen match criteria, CB grafts extend access to transplant for underserved populations, who may not have suitable related or unrelated donors readily available. CB clinical outcomes are steadily improving in experienced transplant centres (TC); furthermore, the robust graft‐versus‐leukaemia effect is particularly beneficial for patients with aggressive leukaemia, making CB the ‘graft of choice’ for these groups. However, many TC have abandoned CB transplants (CBT) because of high cost, medical complexity and (now) lack of expertise. This Nutshell review discusses the role of CB in transplantation and the ongoing efforts to optimize CBT practices and improve CB utilization.

Despite clinical benefit with the use of chimeric antigen receptor (CAR) T cells, the need to manufacture patient-specific products limits its clinical utility. To overcome this barrier, we developed an allogeneic “off-the-shelf” CAR T-cell product using Epstein-Barr virus (EBV)–specific T cells (EBV-VSTs) genetically modified with a CD19-specific CAR (19-28z). Patients with relapsed/refractory (R/R) B-cell malignancies were stratified into 3 treatment cohorts: cohort 1 (n = 8; disease recurrence after allogeneic or autologous hematopoietic cell transplantation [HCT]), cohort 2 (n = 6; consolidative therapy after autologous HCT), or cohort 3 (n = 2; consolidative therapy after allogeneic HCT). The primary objective of this trial was to determine the safety of multiple CAR EBV-VST infusions. Most patients (n = 12/16) received multiple doses (overall median, 2.5 [range, 1-3]) with 3 × 106 T cells per kg determined to be the optimal dose enabling multiple treatments per manufactured cell line. Severe cytokine release syndrome or neurotoxicity did not occur after infusion, and no dose-limiting toxicity was observed in the trial. Median follow-up was 48 months (range, 4-135) with 4 deaths due to disease progression. Overall survival of all patients was 81% at 12 months and 75% at 36 months. Postinfusion expansion and persistence were limited, and CAR EBV-VSTs demonstrated a unique T-cell phenotype compared with autologous 19-28z CAR T cells. Our study demonstrates the feasibility and safety of an allogeneic “off-the-shelf” CAR EBV-VST product with favorable outcomes for patients with CD19+ R/R B-cell malignancies. This trial was registered at www.ClinicalTrials.gov as #NCT01430390.

Despite the global unrelated donor (URD) registry size, the degree to which URD availability is a transplant barrier is not established. We evaluated the availability of 3,843 URDs requested for 455 diverse adult patients (predominantly with acute leukemia). URDs for non-Europeans were more likely to be domestic and had markedly lower Donor Readiness scores. Of URDs requested for confirmatory HLA-typing (CT) alone (ie, without simultaneous workup), 1,894 of 3,529 (54%) were available. Availability of domestic URDs was 45%. Donor Readiness score was highly predictive of CT availability. More non-European patients (n = 120) than Europeans (n = 335) had >10 URDs requested and <5 available. Of workup requests (after CT or CT-workup), <70% (604/889 [68%]) were available. More non-Europeans had <2 URDs available. URD availability for CT was markedly worse for non-Europeans, with availabilities for African, non-Black Hispanic, and Asian patients being 150/458 (33%), 120/258 (47%), and 119/270 (44%), respectively, with further decrements in URD workup availability. Our data suggest the functional size of the URD pool is much smaller than appreciated, mandating major operational changes for transplant centers and donor registries. Likelihood of donor availability should have a high priority in donor selection. Considering patient ancestry and URD Donor Readiness scores, centers should pursue, and registries permit, simultaneous pursuit of many URDs and abandon futile searches. Patients should be informed about their likelihood of donor availability and alternative options. Finally, although registries should address high URD attrition and speed procurement, use of all HLA-disparate graft types is needed to facilitate timely transplant for all.