神田 善伸

Although allogeneic hematopoietic stem cell transplantation (allo-HCT) is considered a potentially curative therapy for multiple myeloma, disease progression after allo-HCT remains a major limitation. Post-transplant maintenance therapy may help reduce the risk of relapse. Lenalidomide, an immunomodulatory agent, has demonstrated efficacy in multiple myeloma, but its use after allo-HCT is limited due to concerns regarding graft-versus-host disease (GVHD). To evaluate the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of lenalidomide when used as maintenance therapy after allo-HCT for multiple myeloma. This was a prospective, multicenter, phase I/II clinical trial conducted from 2014 to 2019. Lenalidomide maintenance therapy was initiated 100-365 days post-allo-HCT. Eligible patients received lenalidomide on days 1-21 of a 28-day cycle for at least four cycles, beginning at 5 mg/day. A standard 3 + 3 dose-escalation design (Fibonacci method) was used to determine DLT and MTD. The study included 10 patients; one was excluded due to early disease progression, leaving nine patients evaluable for toxicity. The phase II portion was not conducted due to expiration of the trial period. The median interval from allo-HCT to initiation of lenalidomide was 244 days (range, 169-330 days). At the 10 mg/day dose level, one patient experienced moderate chronic GVHD meeting the predefined criteria for DLT. No other DLTs occurred, establishing the MTD at 10 mg/day. No acute GVHD was observed. Two additional patients developed mild chronic GVHD, which resolved spontaneously without treatment. The 2-year progression-free survival (PFS) and overall survival (OS) rates from the start of maintenance therapy were 53% and 78%, respectively. Late initiation of lenalidomide maintenance therapy after allo-HCT for multiple myeloma was feasible at a dose of 10 mg/day and was associated with a low incidence of GVHD-related complications. However, further studies are required to confirm treatment efficacy.

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a lethal complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). According to the 2016 European Society for Blood and Marrow Transplantation criteria, SOS/VOD is classified into classical SOS/VOD and late-onset SOS/VOD, but their similarities and differences remain unclear. Here we retrospectively investigated the incidence, risk factors, and impact on transplant outcomes of classical and late-onset SOS/VOD in 16 518 allo-HSCT recipients using the Japanese nationwide registry data. The cumulative incidences of classical and late-onset SOS/VOD were 2.5% and 2.2%, with a median onset of 13 and 42 days after transplantation, respectively. Both patients with classical (hazard ratio [HR], 3.45; 95% CI, 3.07-3.87) and late-onset (HR, 3.98; 95% CI, 3.51-4.51) SOS/VOD had a significantly worse overall survival compared with those without. The risk factors for classical and late-onset SOS/VOD are different. Hepatic comorbidities, high-risk diseases, use of melphalan (MEL), and myeloablative conditioning are associated with both types of SOS/VOD. Whereas poor performance status, a prior history of transplantation, and positive hepatitis C virus are associated with only classical SOS/VOD, allo-HSCT from cord blood or related human leukocyte antigen-haploidentical donors, use of total body irradiation and busulfan (BU), and tacrolimus-based graft-versus-host disease prophylaxis are associated with only late-onset SOS/VOD. In particular, the incidence of late-onset SOS/VOD is much higher in patients receiving both BU- and MEL-containing conditioning regimens. These findings suggest that different monitoring and treatment approaches are necessary for allo-HSCT recipients at high risk for classical and late-onset SOS/VOD.

Allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-matched donors is the gold standard. However, haploidentical stem cell transplantation using posttransplant cyclophosphamide (PTCY-haplo) and cord blood transplants (CBTs) are alternatives when HLA-matched donors are not available. Using Japanese registry data, we evaluated the impact of haploidentical donor age on posttransplant outcomes by comparing PTCY-haplo and CBT. We analyzed data for 5161 patients aged 16 to 70 years who received their first HSCT for acute leukemia, myelodysplastic syndrome, or chronic myeloid leukemia. Haploidentical donors were categorized as "younger" (aged <40 years) or "older" (aged ≥40 years), and the patients were divided into younger (aged <50 years) and older (aged ≥50 years) cohorts. In the older cohort, PTCY-haplo from younger donors had better overall survival (OS; 55.5% vs 50.8%, P = .006), lower nonrelapse mortality (NRM; 17.3% vs 28.6%, P < .001), and higher relapse rates (33.0% vs 24.9%, P = .017) than with CBT. PTCY-haplo from older donors had comparable OS (44.1% vs 50.8%, P = 1.00), NRM (27.3% vs 28.6%, P = 1.00), and relapse (29.2% vs 24.9%, P = .90) to that with CBT. In the younger cohort, PTCY-haplo from younger and older donors showed OS, NRM, and relapse comparable with CBT. In the older cohort, cumulative incidence of acute graft-versus-host disease (GVHD) was higher with CBT than with PTCY-haplo, regardless of donor age. However, in the younger cohort, acute GVHD was lower in PTCY-haplo from younger donors than with CBT. PTCY-haplo from younger donors to older patients offers better clinical outcomes than CBT.

It is uncertain whether FLU/BU4 regimens, classified as myeloablative conditioning (MAC), improve prognosis compared to conventional MAC regimens (conv-MAC) such as CY/TBI and BU/CY. We compared FLU/BU4 with conv-MAC among 6551 patients (FLU/BU4 905, conv-MAC 5646), including acute myeloid leukemia (AML) patients aged 16-59 who received a first allogeneic transplantation from the Japanese nationwide registry. The primary endpoint was overall survival (OS), while secondary endpoints were treatment-related mortality (TRM) and relapse at 3 years. Results indicated comparable OS for conv-MAC regimens among the entire cohort (3-year OS: FLU/BU4 50.4% vs. conv-MAC 55.4%, p < 0.001). Subgroup analysis focusing on elderly patients (aged 50-59) indicated that FLU/BU4 showed a statistically significant improvement in OS (47.0% vs. 42.8%, p = 0.036). Notably, for patients in this cohort transplanted at complete remission (CR), FLU/BU4 demonstrated a substantial advantage over conv-MAC with superior OS (HR 0.75, p = 0.046), lower TRM (HR 0.66, p = 0.035), and comparable relapse (HR 0.84, p = 0.390). These benefits were not observed in elderly patients transplanted at non-CR or in other age groups. In summary, our findings suggest that FLU/BU4 regimen, rather than conv-MAC, may be preferable in MAC-tolerant AML patients, aged 50-59 at CR status. This treatment improves survival by reducing TRM without increasing relapse risk.