Lucila Nassif Kerbauy

Background: Elderly patients are increasingly being offered allogeneic hematopoietic cell transplantation (HCT), and several strategies have been developed to meet their needs. The objective of the current study was to report the feasibility of a reduced-intensity busulfan/fludarabine conditioning regimen with total marrow irradiation in older patients. Methods: This single-center study included 28 patients aged 60–77 years with a median follow-up of 34 months. Results: Overall survival at 2 years was 46%, relapse rate was 30%, and non-relapse mortality was 23%, yielding a progression-free survival of 46%. Rates of grades II-IV acute GVHD, III-IV acute GVHD, and chronic GVHD were 47%, 8%, and 19%, respectively. Only one patient did not achieve neutrophil engraftment. Three patients experienced sinusoidal obstruction syndrome, and all recovered. Causes of death included disease progression ( n = 10), infection ( n = 5, including one COVID-19 case), and acute myocardial infarction ( n = 1). Conclusion: Our results demonstrate the feasibility of an intensified, total marrow irradiation-based conditioning regimen in an elderly cohort, primarily comprising transplants from alternative donors for high-risk diseases. Non-relapse mortality was very low, given the patients’ profile, and compares favorably with others reports reduced-intensity regimen with total body irradiation in older patients. Future studies should compare it to the standard reduced-intensity and non-myeloablative regimens.

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for several malignant hematologic diseases and alternative donors, including haploidentical, play a significant role in HCT. Despite the increasing use of haplo-HCT with PTCy, some questions remain open. The objective of the present study was to investigate risk factors for adverse outcomes after haplo-HCT with PTCy. This is a retrospective study conducted at two Brazilian centers. A total of 103 patients with hematologic malignancies who underwent first allogeneic, haploidentical HCT with PTCy were included. Risk factors for death were age at transplant (HR = 1.03 for each year; p = 0.002) and high/very high disease risk index (DRI; HR = 2.77; p = 0.0007) and mother as the donor compared with other donors (HR = 3.53; p = 0.005). In multivariate analysis, PFS was significantly poorer for older patients (HR = 1.02; p = 0.006), high/very high DRI (HR = 2.39; p = 0.003), and mother as the donor compared with other donors (HR = 3.18; p = 0.006). Relapse rate was higher for high/very high DRI (HR = 4.01; p = 0.002) and mother as the donor compared with other donors (HR = 2.52; p = 0.05). NRM was higher for older patients (HR = 1.03 for each year; p = 0.03). Tacrolimus was a protective factor for grades II–IV aGVHD (HR = 0.46; p = 0.04) compared with cyclosporine. Peripheral blood (PBSC) was a risk factor for cGVHD (HR = 3.48; p = 0.006), while tacrolimus was protective (HR = 0.30; p = 0.009). Mother as the donor compared with other donors was also a risk factor for poorer OS, PFS, and relapse, suggesting that this combination should be avoided. Tacrolimus was protective for both grades II–IV aGVHD and cGVHD, suggesting that tacrolimus may be more effective than cyclosporine in preventing GVHD. PBSC was a risk factor for cGVHD without any impact on relapse. Prospective studies comparing tacrolimus with cyclosporine are awaited.

Glioblastoma multiforme (GBM), the most aggressive brain cancer, recurs because glioblastoma stem cells (GSCs) are resistant to all standard therapies. We showed that GSCs, but not normal astrocytes, are sensitive to lysis by healthy allogeneic natural killer (NK) cells in vitro. Mass cytometry and single-cell RNA sequencing of primary tumor samples revealed that GBM tumor–infiltrating NK cells acquired an altered phenotype associated with impaired lytic function relative to matched peripheral blood NK cells from patients with GBM or healthy donors. We attributed this immune evasion tactic to direct cell-to-cell contact between GSCs and NK cells via αv integrin–mediated TGF-β activation. Treatment of GSC-engrafted mice with allogeneic NK cells in combination with inhibitors of integrin or TGF-β signaling or with TGFBR2 gene–edited allogeneic NK cells prevented GSC-induced NK cell dysfunction and tumor growth. These findings reveal an important mechanism of NK cell immune evasion by GSCs and suggest the αv integrin/TGF-β axis as a potentially useful therapeutic target in GBM.