Nobuhiko Imahashi

Outcomes of allogeneic hematopoietic stem cell transplantation are significantly influenced by conditioning regimens and graft-versus-host disease (GVHD) prophylaxis. Previous studies comparing matched-related donor (MRD) and umbilical cord blood (UCB) transplantation included patients with heterogeneous conditioning regimens and GVHD prophylaxis, potentially obscuring the true effects of donor type. We retrospectively compared outcomes of MRD (n = 1335) and UCB (n = 1097) transplantation performed with conditioning regimens and GVHD prophylaxis considered appropriate for cyclophosphamide/total body irradiation-based transplantation. Multivariable analysis revealed better relapse-free survival (RFS) for UCB than MRD in acute myeloid leukemia (hazard ratio [HR]: 0.80; 95% confidence interval [CI]: 0.65-0.99; P = 0.04) and lymphoma (HR: 0.61; 95% CI: 0.37-0.997; P = 0.04). In contrast, RFS was similar between MRD and UCB in acute lymphoblastic leukemia (HR: 0.97; 95% CI: 0.79-1.18; P = 0.74) and worse for UCB in myelodysplastic syndrome (HR: 1.66; 95% CI: 1.09-2.52; P = 0.01). These findings suggest that, when appropriate regimens are used, UCB may perform more favorably than MRD depending on disease type. Further validation in independent registry studies is warranted.

Fludarabine/busulfan and fludarabine/melphalan are viable options as conditioning regimens. However, the optimal fludarabine‐based conditioning in cord blood transplantation (CBT) remains unclear. Therefore, this retrospective, registry‐based study aimed to analyze the impact of five fludarabine‐containing conditioning regimens on 1395 adult patients (median age, 61 years) with acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia who underwent their first CBT. Treatment outcomes of fludarabine combined with melphalan (100–140 mg/m²) and low‐dose total body irradiation (TBI; FM140T); melphalan (80–99 mg/m²) and TBI (FM80T); busulfan (12.8 mg/kg) and melphalan (FB4M); busulfan (12.8 mg/kg) and TBI (FB4T); and busulfan (6.4 mg/kg) and TBI (FB2T) were compared. The 3‐year survival rate was 67%, 53%, 44%, 36%, and 39%, respectively (p < .0001). The FM140T survival rate was the most favorable after adjusting for confounders, and the hazard ratios (vs. FM140T) for overall mortality were as follows: FM80T, 1.6 (95% confidence interval [CI], 1.2–2.2); FB4M, 2.1 (95% CI, 1.6–2.8); FB4T, 2.7 (95% CI, 2.0–3.7); and FB2T, 2.2 (95% CI, 1.6–3.1). The better survival observed with FM140T, regardless of the disease, disease risk, age, or transplant year, was attributed to the lower relapse rate and lower non‐relapse mortality (NRM) associated with fewer infectious deaths. Conversely, FB4T was associated with a higher relapse rate and higher NRM. The findings indicate that the outcomes of CBT in myeloid malignancies were highly dependent on both the alkylating agent and its dose in combination with fludarabine. Therefore, compared with fludarabine/busulfan‐based conditioning, FM140T may be the preferred regimen.

We retrospectively compared the outcomes of reduced-intensity conditioning (RIC) transplantation from matched related donors (MRD; n = 266), matched unrelated donors (MUD; n = 277), and umbilical cord blood (UCB; n = 513) for mature lymphoid malignancies. The 3-year overall survival rates for the MRD, MUD, and UCB groups were 54%, 59%, and 40%, respectively (P < 0.001). Multivariate analysis showed no differences in survival between the MRD group and the MUD or UCB group. However, survival was significantly affected by the conditioning regimen and graft-versus-host disease (GVHD) prophylaxis in the UCB group, but not in the MRD and MUD groups. Notably, multivariate analysis showed that the risk of overall mortality in the UCB recipients who received the optimal conditioning regimen and GVHD prophylaxis (n = 116) was lower than that in the MRD group (relative risk [RR], 0.69; P = 0.03) and tended to be lower than that in the MUD group (RR, 0.75; P = 0.09). Our results suggest that UCB transplantation performed with the optimal conditioning regimen and GVHD prophylaxis is highly effective. Moreover, UCB is readily available. Thus, UCB transplantation with the optimal conditioning regimen and GVHD prophylaxis is preferable to MUD transplantation when MRD are not available in the setting of RIC transplantation for mature lymphoid malignancies.

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.

To investigate which reduced-intensity conditioning (RIC)/reduced-toxicity conditioning (RTC) is superior for umbilical cord blood transplantation (UCBT) for lymphoid malignancies, we retrospectively compared three widely used RIC/RTC regimens: fludarabine/melphalan/total body irradiation (FM-TBI, n = 524), fludarabine/cyclophosphamide/total body irradiation (FC-TBI, n = 96), and fludarabine/busulfan/total body irradiation or melphalan (FB-based, n = 159). Among patients with acute lymphoblastic leukemia (ALL) (n = 314), there were no differences in overall survival (OS) by conditioning regimen. Among patients with malignant lymphoma (ML) (n = 465), FM-TBI and FC-TBI regimens had similar OS, whereas FB-based regimen had lower OS (hazard ratio [HR], 1.73; P < 0.01) than did FM-TBI regimen due to higher non-relapse mortality (HR, 1.72; P = 0.02). In addition, mycophenolate mofetil-containing GVHD prophylaxis was associated with better OS than methotrexate-containing GVHD prophylaxis among patients who received FM-TBI (HR, 0.65; P = 0.03) and FC-TBI (HR, 0.25; P < 0.01) regimens due to a decreased relapse risk. In summary, our results suggest that all three RIC/RTC regimens have comparable clinical outcomes in ALL, while the FM-TBI or FC-TBI regimens combined with mycophenolate mofetil-containing GVHD prophylaxis is preferable in RIC/RTC-UCBT for ML. Large prospective studies are warranted to confirm these results.