仲宗根 秀樹

The effects of donor characteristics on outcomes after T-cell-replete (TCR) haploidentical donor peripheral blood stem cell transplantation (PBSCT) with post-transplant cyclophosphamide (PTCy) or low-dose antithymocyte globulin (ATG) remain unclear. We evaluated the impact in 1,677 patients who received a PTCy protocol (PTCy-haplo; n = 1,107) or low-dose ATG protocol (ATG-haplo; n = 570). A low CD34+ cell dose (<4 ×106/kg) was the only donor characteristic associated with worse overall survival (OS) after PTCy-haplo (adjusted hazard ratios [aHR] = 1.49, P = 0.008), whereas increasing donor age by decade (aHR = 1.12, P = 0.008) and human leukocyte antigen 2-3 antigen mismatches (aHR = 1.46, P = 0.010), compared to HLA 0-1 antigen mismatches, were associated with worse OS after ATG-haplo. Increasing donor age was associated with a high risk of grade III-IV acute GVHD both after PTCy-haplo (HR: 1.32, P = 0.009) and ATG-haplo (HR: 1.22, P = 0.006). Offspring donors had better relapse-free survival and GVHD-free relapse-free survival than sibling donors after ATG-haplo. Our data highlights the donor characteristics associated with improved transplant outcomes after TCR haploidentical donor PBSCT with PTCy or low-dose ATG.

BACKGROUND: Patients with adult T-cell leukemia/lymphoma (ATL) are considered to have worse outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT) than patients with other hematological malignancies, owing to high risk of relapse and immunocompromised status. However, no studies have compared transplant outcomes between patients with ATL and those with other hematological malignancies using a large-scale database. OBJECTIVES: To compare transplant outcomes between patients with ATL and those with other leukemias and to identify factors contributing to worse transplant outcomes in ATL patients. STUDY DESIGN: Using Japanese registry data, we retrospectively compared transplant outcomes between patients with ATL and those with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). As ATL often develops in patients in their 60s or older, patients with ATL, AML, or ALL aged ≥50 years were included in order to compare patients in the same age group. A total of 7764 patients (ATL, n = 1151; AML, n = 5393; ALL, n = 1220) who underwent their first allo-HSCT between January 1, 2006 and December 31, 2017 were included in this study. RESULTS: Compared with AML, ATL showed significantly worse overall survival (OS) (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.14 to 1.34; P < .001) and higher risk of relapse (HR, 1.33; 95% CI, 1.2 to 1.47; P < .001), while there were no significant differences between AML and ALL. Among patients in complete remission (CR) at transplantation, ATL showed worse OS (HR, 1.30; 95% CI, 1.08 to 1.56; P = .006), higher risk of relapse (HR, 1.78; 95% CI, 1.48 to 2.14; P < .001), and higher risk of nonrelapse mortality (NRM) (HR, 1.38; 95% CI, 1.14 to 1.33; P = .001) in comparison with AML, whereas there were no significant differences between AML and ALL. CONCLUSION: We found that ATL patients have poor transplant outcomes compared with AML or ALL patients. In ATL patients, survival is poor, relapse is more frequent, and NRM is significantly higher, especially in cases of CR. These findings suggest that prevention of relapse and transplant-related complications is important for successful allo-HSCT in ATL.

Rapid tapering of cyclosporine (CsA) in the early phase after allogeneic transplantation may induce a potent graft-versus-leukemia/lymphoma (GVL) effect. We retrospectively reviewed the outcomes of patients with high-risk hematological malignancies who underwent their first transplantation at our institution. The blood CsA concentration was maintained at around 300 ng/ml. Our planned schedule for tapering CsA in patients without graft-versus-host disease (GVHD) or with limited GVHD was to reduce the dose by 10% per week starting from day 30 for related HSCT or from day 50 for unrelated HSCT. In total, we began tapering CsA in 36, and classified them into 2 an "On-schedule group" or "Delayed group" based on the timing of starting tapering. The cumulative incidences of grade II-IV acute GVHD overall were 33.8% and 39.4% (P = 0.746) in the On-schedule and Delayed groups. The On-schedule group showed no significant difference in non-relapse mortality, but showed a trend toward a higher relapse rate, resulting in significantly worse overall survival (55.6% vs 72.2% at 1y, P = 0.025) and worse disease-free survival (38.9% vs 66.7% at 1y, P = 0.059). These findings suggest that early CsA tapering after HSCT in high-risk patients was not effective.

Fludarabine and myeloablative busulfan (FluBu4) in allogeneic hematopoietic stem cell transplantation (HSCT) for older people have not been adequately examined. This retrospective study analyzed data from a large-scale, nationwide database in Japan. Adult patients (> 15 years old, y/o) who received their first HSCT with FluBu4 for hematological malignancies were included. They were categorized into the younger (< 60 y/o, N = 1295) and the older group (≥ 60 y/o, N = 993). The 3-year overall survival (OS) rate after HSCT was significantly worse in the older group than in the other (p < 0.01, 39.9% vs. 48.5%). The 3-year non-relapse mortality (NRM) was significantly higher in the older group than in the other (p < 0.01, 30.9% vs. 23.0%), and the 3-year cumulative incidence of relapse was comparable between them. According to the multivariate analysis, age ≥ 60 years was significantly associated with poor OS and high NRM. In a subgroup analysis of the older group, the use of additional chemotherapeutic drugs to FluBu4 was significantly associated with poor OS and high NRM. Total body irradiation was significantly associated with high NRM and 1-year incidence of sinusoidal obstruction syndrome but not with OS. Thus, FluBu4 should be used with caution in older people.

In unrelated allogeneic hematopoietic cell transplantation (allo-HCT), older and/or HLA-mismatched donors are known risk factors for survival outcomes. In healthy individuals, cytomegalovirus (CMV) seropositivity is associated with impaired adaptive immune systems. We assessed whether the adverse effects of donor risk factors are influenced by the donor CMV serostatus. We analyzed 5836 CMV seropositive patients who received unrelated allo-HCT. We divided the entire cohort into two cohorts according to the donor CMV serostatus: CMV-positive (DP) and -negative (DN). We also stratified each cohort into four groups based on donor age (≥ 40 or < 40) and HLA parity (8/8 or 7/8): Young88, Old88, Young78, and Old78. In the CMV-DP cohort, the Old88 (HR 1.20, P = 0.012), Young78 (HR 1.35, P < 0.001), and Old78 (HR 1.60, P < 0.001) groups were associated with inferior OS compared with the Young88 group. On the other hand, in the CMV-DN cohort, neither donor age nor HLA disparity was associated with inferior OS. The adverse impact of donor age was different between the cohorts (CMV-DP; HR 1.19, P = 0.001, CMV-DN; HR 1.04, P = 0.53; P for interaction 0.070), as was the impact of HLA (CMV-DP; HR 1.34, P < 0.001, CMV-DN; HR 1.08 P = 0.23; P for interaction 0.012). The impacts of donor age and HLA mismatch on OS might differ according to the donor CMV serostatus. In unrelated allo-HCT from a CMV seronegative donor, an HLA-mismatched older donor may be able to be selected without affecting OS.