Donor selection contributes to improve clinical outcomes of T-cell–replete haploidentical stem cell transplantation (haplo-SCT) with posttransplant cyclophosphamide (PT-Cy). The impact of donor age and other non-HLA donor characteristics remains a matter of debate. We performed a multicenter retrospective analysis on 990 haplo-SCTs with PT-Cy. By multivariable analysis, after adjusting for donor/recipient kinship, increasing donor age and peripheral blood stem cell graft were associated with a higher risk of grade 2 to 4 acute graft-versus-host-disease (aGVHD), whereas 2-year cumulative incidence of moderate-to-severe chronic GVHD was higher for transplants from female donors into male recipients and after myeloablative conditioning. Increasing donor age was associated with a trend for higher nonrelapse mortality (NRM) (hazard ratio [HR], 1.05; P = .057) but with a significant reduced risk of disease relapse (HR, 0.92; P = .001) and improved progression-free survival (PFS) (HR, 0.97; P = .036). Increasing recipient age was a predictor of worse overall survival (OS). Risk of relapse was higher (HR, 1.39; P < .001) in patients aged ≤40 years receiving a transplant from a parent as compared with a sibling. Moreover, OS and PFS were lower when the donor was the mother rather than the father. Pretransplant active disease status was an invariably independent predictor of worse clinical outcomes, while recipient positive cytomegalovirus serostatus and hematopoietic cell transplant comorbidity index >3 were associated with worse OS and PFS. Our results suggest that younger donors may reduce the incidence of aGVHD and NRM, though at higher risk of relapse. A parent donor, particularly the mother, is not recommended in recipients ≤40 years.

Allogeneic hematopoietic stem cell transplantation (SCT) represents a potential curative strategy for patients with Hodgkin lymphoma (HL) relapsing after autologous SCT (ASCT), but the incidence of disease relapse is still high. We performed a retrospective study on 64 patients with HL relapsing after ASCT to compare outcomes after HLA-identical SCT (HLAid-SCT; n = 34) and haploidentical SCT with post-transplantation cyclophosphamide (PT-Cy) (Haplo-SCT; n = 30). All patients engrafted, with a significantly shorter median time for neutrophil and platelet engraftment after HLAid compared with Haplo-SCT (14 days versus 19 days and 11 days versus 23 days, respectively; P < .005). With a median follow-up of 47 months, 3-year overall survival (OS), 3 -year progression-free survival (PFS), and 1-year nonrelapse mortality (NRM) were 53%, 44% and 17%, respectively. Recipients of Haplo-SCT were less likely to experience disease relapse (3-year cumulative incidence of relapse, 13% versus 62%; P = .0001) and chronic graft- versus-host disease (GVHD; 3% versus 32%; P = .003), resulting in improved PFS (60% versus 29%; P = .04) and GVHD-free/relapse-free survival (47% versus 17%; P = .06). The 3-year OS did not differ between the 2 groups (56% versus 54%; P not significant), and NRM was higher after Haplo-SCT, but the difference did not reach statistical significance (26% versus 9%; P = .09). On multivariate Cox regression analysis, receipt of Haplo-SCT (hazard ratio [HR], .17; P = .02) and achieving optimal disease control (complete remission before SCT: HR, .6; P < .0001) were the only independent variables associated with a reduced risk of disease relapse. Haplo-SCT is a valid option for patients with HL relapsing after ASCT, with a reduced incidence of relapse compared with HLAid SCT.

Despite the impressive results of chimeric antigen receptor (CAR) T cell treatment for lymphomas, adverse events such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and infections are major issues that can lead to intensive care unit (ICU) admission and death. Current guidelines recommend tocilizumab for treating patients with CRS grade (G) ≥2; however, the optimal timing of intervention has yet to be determined. Our institution adopted the preemptive use of tocilizumab in cases of persistent G1 CRS, defined as fever (≥38 °C) for >24 hours. This preemptive tocilizumab treatment aimed to reduce evolution to severe (G≥3) CRS, ICU admission, or death. We report on 48 prospectively collected consecutive patients with non-Hodgkin lymphoma treated with autologous CD19-targeted CAR T cells. In total, 39 patients (81%) developed CRS. CRS started as G1 in 28 patients, as G2 in patients, and as G3 in 1 patient. Tocilizumab was administered in 34 patients, including 23 patients who received "preemptive" tocilizumab and 11 patients who received tocilizumab for G2 or G3 CRS from the onset of symptoms. CRS resolved without worsening severity in 19 patients out of 23 (83%) who received preemptive tocilizumab; 4 patients (17%) progressed from G1 to G2 for the development of hypotension and quickly responded to the introduction of steroids. No patients treated with a preemptive approach developed G3 or G4 CRS. Ten out of 48 patients (21%) were diagnosed with ICANS, including 5 patients with G3 or G4. Six infectious events occurred. The overall ICU admission rate was 19%. ICANS management was the most relevant reason for ICU admission (7 patients), and no patient required ICU to manage CRS. No deaths from CAR-T toxicity were observed. Our data indicate that preemptive tocilizumab use is feasible and useful in reducing severe CRS and CRS-related ICU admission, with no impact on neurotoxicity or infection rate. Therefore, early use of tocilizumab can be considered, especially for patients at high risk of CRS.

Haploidentical hematopoietic stem cell transplantation (h-HSCT) represents an efficient curative approach for patients affected by hematologic malignancies in which the reduced intensity conditioning induces a state of immunologic tolerance between donor and recipient. However, opportunistic viral infections greatly affect h-HSCT clinical outcomes. NK cells are the first lymphocytes that recover after transplant and provide a prompt defense against human cytomegalovirus (HCMV) infection/reactivation. By undertaking a longitudinal single-cell computational profiling of multiparametric flow cytometry, we show that HCMV accelerates NK cell immune reconstitution together with the expansion of CD158b1b2j ^pos /NKG2A ^neg /NKG2C ^pos /NKp30 ^lo NK cells. The frequency of this subset correlates with HCMV viremia, further increases in recipients experiencing multiple episodes of viral reactivations, and persists for months after the infection. The transcriptional profile of FACS-sorted CD158b1b2j ^pos NK cells confirmed the ability of HCMV to deregulate NKG2C, NKG2A, and NKp30 gene expression, thus inducing the expansion of NK cells with adaptive traits. These NK cells are characterized by the downmodulation of several gene pathways associated with cell migration, the cell cycle, and effector-functions, as well as by a state of metabolic/cellular exhaustion. This profile reflects the functional impairments of adaptive NK cells to produce IFN-γ, a phenomenon also due to the viral-induced expression of lymphocyte-activation gene 3 (LAG-3) and programmed cell death protein 1 (PD-1) checkpoint inhibitors.