稲本 賢弘

Adult T-cell leukemia-lymphoma (ATL) is one of the most intractable peripheral T-cell neoplasms caused by human T-cell leukemia virus type I (HTLV-1) infection. Recently, the incidence of HTLV-1 infection and ATL has increased in non-endemic metropolitan areas in Japan. This retrospective study evaluated the clinical features and outcomes of patients with aggressive ATL aged 70 years or younger treated at a core hospital in Tokyo between 2004 and 2016. The median follow-up was 124.4 months for survivors. Among the 71 patients, 46 (64.8%) underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). The 3 year overall survival rate was 45.7% in allo-HSCT group versus 0% in non-allo-HSCT group. Patients who achieved complete/partial remission before allo-HSCT had a significantly better survival rate than those with stable/progressive disease (51.4% vs 27.3%). The 2 year cumulative incidence of relapse/progression and non-relapse mortality after allo-HSCT was 41.3% and 21.7%, respectively. In this study, a large percentage of patients underwent allo-HSCT and achieved favorable outcomes. As cases continue to rise in metropolitan areas, core hospitals will play a critical role in ATL treatment.

The optimal alternative donor type for patients lacking human leucocyte antigen (HLA)-matched related or unrelated donors remains unclear. In comparative studies evaluating donor types, graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) represents a well-established end-point but has limitations. The win ratio approach addresses these limitations by analysing multiple end-points with varying severities to account for the relative component priorities. We compared HLA-mismatched unrelated donors, haploidentical donors and cord blood using both the hazard ratio (HR) of GRFS and the win ratio related to GRFS. The haploidentical donor group had a similar HR of GRFS (HR: 1.01, 95% confidence interval [CI]: 0.85-1.19, p = 0.916) and win ratio (win ratio: 0.86, 95% CI: 0.72-1.02, p = 0.081) to HLA-mismatched unrelated donors. Cord blood transplantation showed similar GRFS compared to HLA-mismatched unrelated donors in the Cox proportional model (HR: 1.14, 95% CI: 0.98-1.32, p = 0.085), significantly lower win ratio (win ratio: 0.80, 95% CI: 0.68-0.93, p = 0.004) and similar outcomes to haploidentical donors. HLA-mismatched unrelated donor transplantation showed comparable to superior outcomes among alternative donor types. Our results indicate the need to present the win ratio alongside conventional methods to assess the end-point robustly.

Overall response (OR) that combines complete (CR) and partial responses (PR) at day (D) 28 is the conventional endpoint for acute GVHD trials. Since PR includes heterogeneous clinical presentations, reclassifying PR could produce a better endpoint. Patients in the primary treatment cohort from JSTCT were randomly divided into training and validation sets. In the training set, a classification and regression tree algorithm generated D28 refined response (RR) criteria based on symptoms at treatment and D28. We then compared RR for primary and second-line treatments to conventional criteria, using the area under the receiver operating curve (AUC) and negative predictive value (NPV) for 6-month non-relapse mortality as performance measures. RR considered patients with grade 0/I at D28 without additional treatment as responders. RR for primary treatment produced higher AUCs than OR with small improvement of NPVs in both validation sets: JSTCT (AUC: 0.73 vs. 0.69, P<0.001; NPV: 92.0% vs. 89.6%, P<0.001) and MAGIC (AUC: 0.71 vs. 0.68, P=0.032; NPV: 90.9% vs. 89.8%, P=0.009). RR for second-line treatment produced similar AUCs but much higher NPVs than OR in both validation sets of JSTCT (AUC: 0.64 vs. 0.63, P=0.775; NPV: 74.5% vs. 66.0%, P<0.001) and MAGIC (AUC: 0.67 vs. 0.64, P=0.105; NPV: 86.8% vs. 76.1%, P=0.004). Classifying persistent, but mild skin symptoms as responses and residual lower GI GVHD as non-responses were major drivers in improving the prognostic performance of RR. Our externally validated D28 RR would serve as a better endpoint than conventional criteria in future first- and second-line treatment trials.

Letermovir, a moderate inhibitor of CYP3A4 and inducer of CYP2C9 and CYP2C19, is used for cytomegalovirus prophylaxis following allogeneic hematopoietic stem cell transplantation (HCT). Posaconazole also inhibits CYP3A4, affecting tacrolimus metabolism. This study aimed to examine tacrolimus conversion ratios when switching from continuous intravenous to oral administration in HCT patients receiving posaconazole with and without letermovir. Tacrolimus concentration-to-dose (C/D) ratios before (C/Dciv) and after (C/Dpo) conversion were compared. The median C/Dciv ratios were 20.1 and 22.5 (ng/mL)/(mg/day) for patients with and without letermovir, respectively (P = 0.31). The median C/Dpo ratios were 5.1 and 5.9 (ng/mL)/(mg/day), respectively (P = 0.43). The median (C/Dpo)/(C/Dciv) ratios were 0.25 and 0.24, respectively (P = 0.77), indicating no significant difference in tacrolimus conversion ratios with and without letermovir. Based on these findings, the tacrolimus conversion ratio in patients receiving posaconazole was estimated to be approximately 1:2, regardless of concomitant letermovir use.