All-trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) has become the international standard of care for newly diagnosed acute promyelocytic leukemia (APL), demonstrating superior efficacy and safety over ATRA-chemotherapy regimens. However, in Japan, ATO has been approved only for relapsed/refractory APL, and prospective data on its frontline use are lacking. We conducted FBMTG-APL2017, a prospective multicenter phase II trial in Japan, to evaluate ATRA-ATO in newly diagnosed APL patients, including both low-intermediate-risk and high-risk groups. Eighty-one patients were enrolled between 2017 and 2021 and treated with ATRA plus delayed ATO during induction, followed by four cycles of ATRA-ATO consolidation. Complete remission was achieved in 95.1% of patients. With a median follow-up of 55 months, 3-year disease-free survival (DFS) and overall survival (OS) were 93.6% and 95.0%, respectively, consistent with international ATRA-ATO trials. DFS was 96.9% in low-intermediate-risk and 80.0% in high-risk patients, with no significant difference. Molecular remission was achieved in 99% after consolidation, and only two molecular relapses occurred. Differentiation syndrome developed in 56.8% but was generally manageable, with only one fatal case; early death occurred in 4.9%, comparable to international data. These results provide the first prospective evidence in Japan that frontline chemo-free ATRA-ATO is highly effective and safe across all risk groups. They support its adoption as a new standard therapy and bridge the gap with established global practice. Trial Registration: Japan Registry of Clinical Trials: jRCTs071180040.

Background: Cord blood is an alternative donor source for patients without HLA-matched donors. Calcineurin inhibitors (CNIs) alone, as prophylaxis for graft-versus-host disease (GVHD) in cord blood transplantation (CBT) patients, reportedly increase the incidence of severe pre-engraftment immune reaction (PIR), leading to transplant-related mortality (TRM) with primary engraft failure and multiple organ dysfunctions. Therefore, additional immunosuppressive agents are needed. Reportedly, short-term methotrexate (sMTX) plus CNIs improved outcomes in patients receiving CBT with full-intensity conditioning (FIC) regimens; however, safety and efficacy of sMTX plus cyclosporine have not been assessed in patients receiving CBT with reduced-intensity conditioning (RIC) regimens. Methods: We retrospectively analyzed 43 patients who received single-unit CBT and were treated with sMTX plus cyclosporine (RIC group, 15; FIC group, 28). Results: Neutrophil engraftment rate was significantly lower in RIC group (53.3%) than in FIC group (78.6%, P=0.04). Cumulative incidence of TRM tended to be higher in the RIC group than in the FIC group (P=0.12); the leading cause of death in the RIC group was bacterial infections. Conclusions: sMTX plus cyclosporine does not seem feasible for treating patients receiving single-unit CBT following RIC. MTX dose optimization or alternative immunosuppressive agent application should be considered in such patients.

Adult T cell leukemia/lymphoma (ATL) is a highly aggressive hematologic malignancy with a very poor prognosis, and most patients with ATL are elderly. Although post-transplantation cyclophosphamide (PTCy) has yielded promising results in various diseases, available data are limited regarding its outcomes in ATL. The aim of this study was to determine the safety and efficacy of reduced-intensity peripheral blood stem cell transplantation (PBSCT) from a human leukocyte antigen (HLA)-haploidentical donor using PTCy as graft-versus-host disease (GVHD) prophylaxis. This was a prospective, multicenter phase I/II study (UMIN000021783) conducted at 16 hospitals in Japan. The primary endpoint was the probability of survival with engraftment and without grade III/IV acute GVHD at day 60 after PBSCT. The expected probability of the primary endpoint was estimated to be 60%, and the threshold probability was set at 30% on the basis of previous studies. The conditioning regimen consisted of fludarabine (30 mg/m2/d from day –7 to –2), melphalan (40 mg/m2/d on days –3 and –2), and total body irradiation (2 Gy on day –1). GVHD prophylaxis consisted of tacrolimus starting at 0.02 mg/kg/d on day –1, PTCy (50 mg/kg/d on days +3 and +5), and mycophenolate mofetil 2000 mg/d starting on day +6. Eighteen ATL patients underwent PBSCT. The probability of patients who met the primary endpoint was 89% (95% confidence interval, 65% to 99%). The cumulative incidences of grade II to IV acute GVHD, III/IV acute GVHD, and moderate-to-severe chronic GVHD were 39%, 11%, and 17%, respectively. The probabilities of overall survival were 83% at 1 year and 73% at 2 years. The cumulative incidences of non-relapse mortality and disease progression at 1 year were 11% and 28%, respectively. HLA-haploidentical PBSCT with PTCy as GVHD prophylaxis is a valid option for patients with aggressive ATL.

Introduction: Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T-cell lymphoma caused by human T-cell lymphotropic virus type I. In younger patients, allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to improve prognosis through a graft-versus-ATL (GvATL) effect. On the other hand, elderly patients with ATL are often not amenable to HSCT, and the prognosis is extremely poor with existing chemotherapy. The most widely used chemotherapy for ATL, CHOP (combination of cyclophosphamide-doxorubicin-vincristine-prednisone) and similar chemotherapy, have shown a complete response (CR) rate of about 20% and a long-term prognosis of less than 10%. In a phase II study of mogamulizumab, a humanized defucosylated anti-C-C chemokine receptor 4 monoclonal antibody, in concurrent combination with chemotherapy (mLSG15), the primary endpoint of CR was 52% in the mLSG15 + mogamulizumab group compared to 33% in the mLSG15 alone group. However, no improvement was observed in overall survival (OS) or progression-free survival (PFS). In addition, mLSG15 is a potent chemotherapy and not feasible in majority of elderly patients. Considering the possibility that mogamulizumab may unlock the tumor immune evasion mechanism by removing regulatory T cells and exert an immunological effect like GvATL, we investigated its usefulness as an immunological consolidation therapy following chemotherapy, with the aim of suppressing recurrence.

In the original publication of the article, the "CNS involvement" in the last row under the column "Total N=50" has been published incorrectly. The correct Table 1 is given in this correction.

The effects of stem cell transplantation (SCT) in patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) remain controversial. We analyzed the feasibility of SCT and risk factors associated with outcomes of PTCL-NOS and AITL patients to identify the potential clinical efficacy of SCT. We retrospectively analyzed the data of PTCL-NOS (n = 83) and AITL (n = 112) patients who received autologous (n = 10 and 16, respectively) or allogeneic (n = 12 and 4, respectively) SCT, or no SCT (n = 61 and 92, respectively) between 2008 and 2018. All PTCL-NOS and AITL diagnoses were reconfirmed by an experienced hematopathologist. Median age at PTCL-NOS and AITL diagnoses in the SCT group was younger than that in the no SCT group. Significant risk factors for lower overall survival were intermediate–high and high-risk international prognostic indexes in PTCL-NOS patients (P = 0.0052), and a > 2 modified prognostic index for T-cell lymphoma (P = 0.0079) and no SCT (P = 0.028) in AITL patients. Autologous or allogeneic SCT compared with no SCT in AITL patients resulted in 3-year overall survival of 68.6% and 100% vs. 57.2% (P = 0.018). Strategies should be developed to improve selection of PTCL-NOS and AITL patients suitable for SCT and/or additional novel therapies.

A novel anti-cytomegalovirus (CMV) agent, letermovir (LMV), could reportedly improve the outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) recipients because of its high potential to prevent CMV reactivation. Therefore, 685 Japanese allo-HCT recipients, of whom ~80% had a high risk of CMV reactivation, were retrospectively analyzed to assess the impacts of prophylactic LMV on the incidence of clinically significant CMV (csCMV) infection as well as their transplant outcome. By comparing 114 patients who received LMV prophylaxis for a median 92 days to 571 patients without prophylaxis, we observed that prophylactic LMV could significantly (1) reduce the 180-day cumulative incidence of csCMV infection (44.7 vs. 72.4%, p < 0.001), (2) delay the median time until initiation of CMV antigenemia-guided preemptive therapy (90 vs. 36 days, p < 0.001), (3) shorten the duration of anti-CMV preemptive treatment (21 vs. 25 days, p = 0.006), and (4) improve the overall survival rate at 180 days after transplant (80.4 vs. 73.0%, p = 0.033) with a trend of lower non-relapse mortality (8.9 vs. 14.9%, p = 0.052). Our findings demonstrate that prophylactic LMV treatment is highly effective in preventing the development of csCMV infection and ultimately reduces transplant-related mortality.

Adequate hematopoietic progenitor cell collection is critical for autologous peripheral blood stem cell transplantation. Conventionally, patients with multiple myeloma are treated with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) or G-CSF alone to mobilize their peripheral blood stem cells. However, some patients exhibit insufficient stem cell recruitment in response to these regimens. Recently, plerixafor has been approved for coverage by insurance in Japan. Combination treatment with plerixafor and G-CSF is now a standard procedure. In addition, treatment with bortezomib and G-CSF results in efficient stem cell recruitment. On the basis of the results from mouse studies, we hypothesized that combination treatment with bortezomib ensures efficient mobilization and mediates in vivo purging of malignant cells. Therefore, we administered a regimen of bortezomib, G-CSF, and preemptive plerixafor to 10 patients with multiple myeloma, and analyzed its efficacy and safety. The median patient age was 68 years. We collected CD34-positive cells (median: 4.9×106/kg) in a single session of apheresis from all patients. We observed no obvious myeloma cell contamination in the collected product or serious toxicity during treatment and collection. After collection, we performed autologous peripheral blood stem cell transplantation and confirmed engraftment in all patients (median: day 10). We found that the regimen is safe and reliably facilitated the collection of sufficient autologous peripheral blood stem cells by apheresis from all patients in a single day. Despite the small patient group size, we conclude that the regimen is promising for safe and efficient collection of peripheral blood stem cells for autologous transplantation in patients with multiple myeloma.

Epstein-Barr virus (EBV) is a common virus that latently infects most adults and has a tropism to B lymphocytes. In 1988, two cases of EBV infection were reported to be eradicated by hematopoietic stem cell transplantation from an EBV-negative donor. However, the dynamics of EBV after cord blood transplantation (CBT), namely, the kinetics of anti-EBV antibodies, the incidence of negative/adverse seroconversion (from positive to negative), and the clinical course of re-infection (second primary infection) by EBV, have not yet been characterized in detail. Therefore, we performed a nationwide survey that focused on the dynamics of EBV after CBT 1 year or later after CBT. Negative seroconversion occurred in 23% of previously EBV-infected patients. The incidence of late-onset EBV-associated events was 1.9% (13/674): 5 infectious mononucleosis, 2 hemophagocytic lymphohistiocytosis (HLH), and 6 remaining typical lymphoproliferative disease. HLH occurred in newly infected patients (primary or second primary) and also in those with reactivation and was fatal. The annual monitoring of anti-EBV antibody titers may facilitate the early detection of these late-onset EBV-associated events and treatment initiation before disease progression.

Umbilical cord blood transplantation (UCBT) is a curative treatment for hematological malignancies. However, appropriate prophylaxis against graft-versus-host disease (GVHD), aimed at obtaining rapid and stable engraftment and avoiding toxicity, remains controversial in UCBT. We retrospectively compared outcomes in 409 patients who received calcineurin inhibitors (CIs) plus conventional-dose methotrexate (conv-MTX/CIs, n = 77; methotrexate, 10 mg/m2 on day 1, 7 mg/m2 on days 3 and 6) with those who received CIs plus reduced-dose methotrexate (reduced-MTX/CIs, n = 209; methotrexate, 5 mg/m2 or 5 mg/body on days 1, 3, and 6) or CIs with mycophenolate mofetil (MMF/CIs, n = 123) for GVHD prophylaxis after UCBT. The cumulative incidence of neutrophil engraftment was significantly higher in the reduced-MTX/CI (82.3%) and MMF/CI (86.6%) groups than the conv-MTX/CI (71.4%) group (p = 0.014), although there were no differences in platelet recovery or infectious complications among the three groups. The incidence and severity of GVHD were comparable among the three groups, and there were no significant differences in transplantation-related mortality among the three groups. In conclusion, GVHD prophylaxis with reduced-dose methotrexate and MMF was closely associated with high incidence of neutrophil engraftment without an effect on the incidence and severity of GVHD, which was compared to GVHD prophylaxis with conventional-dose methotrexate.

Outcomes for patients with multiple myeloma (MM) have improved through use of novel treatments, especially lenalidomide combined with autologous stem cell transplantation. However, because of their increased life expectancy, an increased risk of secondary primary malignancies (SPMs) has been observed in MM patients, particularly after lenalidomide maintenance in both transplant-eligible (TE) and transplant-ineligible (TI) patients. To evaluate the incidence and risk factors of developing SPMs, we identified 17 TE-MM and 12 TI-MM patients with SPMs among 211 TE-MM and 280 TI-MM patients, including seven TE-MM and four TI-MM patients with hematological malignancies and ten TE-MM and eight TI-MM patients with non-hematological cancers, respectively. The median follow-up time from diagnosis was > 4 years. Multivariate analysis identified a history of high-dose cyclophosphamide use for peripheral blood stem cell harvest in TE-MM patients and > 65 years of age at diagnosis, or a history of adriamycin, lenalidomide, or thalidomide use in TI-MM patients as independent risk factors for SPMs (P < 0.001). Patients with a history of lenalidomide use had a lower risk of death among both TE-MM (P = 0.0326) and TI-MM (P < 0.001) patients. The survival benefit of receiving lenalidomide outweighed the increased risk of SPMs in both TE-and TI-MM patients.

Background: The prognosis of allogeneic hematopoietic stem cell transplantation (HSCT) for non-remission hematological malignant diseases is usually unfavorable. The most uncontrollable factor is residual disease or relapse. To overcome this problem, intensified conditioning regimens- sequential and/or additional chemotherapy to the standard regimen- could be effective. However, increasing the intensity of conditioning might also lead to more complications. Materials and Methods: We retrospectively analyzed 81 patients with non-remission disease who received allogeneic HSCT in our institution between 2007 and 2011. Results: 55.6% in 36 myeloablative conditioning patients and 46.7% in 45 reduced-intensity conditioning patients received intensified conditioning. The 5-year probability of overall survival was 35.0% and 17.1% in the standard and intensified group, respectively (p=0.027). Relapse mortality was 30% in the standard regimen group and 36.6% in the intensified regimen group (p=0.54). Transplant-related mortality (TRM) at 30 and 100 days was 5%, 17.1% (p=0.086) and 27.5%, 34.2% (p=0.52) in the standard and intensified group, respectively. There was no difference in TRM between the 2 groups at 30 days and 100 days. Conclusion: The results of the study confirm the safety of the intensified conditioning regimen. Meanwhile, it could be considered as one of the few methods available to reduce the tumor burden before HSCT for refractory malignant diseases.

This study aimed at determining how cytogenetic risk status affects outcomes for patients with acute myeloid leukemia (AML) after undergoing various types of allogeneic hematopoietic cell transplantation (HCT). Of 7812 patients eligible for analysis, cytogenetic risk was classified as favorable for 1088, intermediate for 5025, and poor for 1699. Overall, multivariate analysis showed significant intergroup differences in terms of relapse and survival, with the difference between poor- and intermediate-risk groups being greater than that between favorable- and intermediate-risk groups. Non-relapse mortality was identical for the three groups. Significant effects of cytogenetic risk status on survival were documented irrespective of donor type (related, unrelated, and umbilical cord blood), disease status at the time of transplantation (first or second complete remission, and more advanced disease status), and conditioning intensity (myeloablative and reduced-intensity). Our findings demonstrate robust and constant effects of cytogenetic risk status on survival after allogeneic HCT for patients with AML.

Graft gamma delta T-cell receptor sequencing identifies public clonotypes associated to HSCT efficacy in AML patients and unravels CMV impact on repertoire distribution

We prospectively compared outcomes of autologous stem cell transplantation (ASCT) versus high-dose cytarabine (HiDAC) consolidation as post-remission therapy for favorable- and intermediate-risk acute myelogenous leukemia (AML) in first complete remission (CR1). Two-hundred-forty patients under 65 years with AML-M1, M2, M4, or M5 subtypes were enrolled. After induction, 153 patients did not undergo randomization, while the remaining 87 who achieved CR1 were prospectively randomized to HiDAC (n = 45) or ASCT arm (n = 42). In the HiDAC arm, 43 patients completed three cycles of HiDAC, whereas in ASCT arm 22 patients completed two cycles of consolidation consisting of intermediate-dose cytarabine plus mitoxantrone or etoposide followed by ASCT. The three-year disease-free survival (DFS) rate was 41% in HiDAC and 55% in ASCT arm (p = 0.25). Three-year overall survival (OS) rates were 77 and 68% (p = 0.67). Incidence of relapse was 54 and 41% (p = 0.22). There was no significant difference in nonrelapse mortality between two arms (p = 0.88). Patients in the ASCT arm tended to have higher DFS rates and lower relapse rates than patients in HiDAC; however, there was no significant improvement in OS in patients with favorable- and intermediate-risk AML in CR1. Patients with AML are not benefited by the intensified chemotherapy represented by ASCT.

We conducted a retrospective registry-based study involving 198 patients with acute promyelocytic leukemia (APL) who underwent autologous hematopoietic cell transplantation (HCT) during second complete remission (CR2) from 1995 to 2012. Arsenic trioxide (ATO) became commercially available in Japan in December 2004, and a substantial increase in the annual numbers of transplantations has occurred since 2005. Patients transplanted after 2006 had significantly better relapse-free and overall survival than those transplanted before 2004 (p = .028 and p = .027, respectively). There was a significant difference in cumulative incidence of relapse in favor of those transplanted after 2006 (p = .008), whereas non-relapse mortality did not differ between the two groups (p = .683). Our findings suggest that the introduction of ATO may have reduced post-transplantation relapse without increasing non-relapse mortality, resulting in significant improvements in overall outcomes for relapsed APL patients undergoing autologous HCT during CR2.

Mogamulizumab (MOG), a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, has recently played an important role in the treatment of adult T cell leukemia/lymphoma (ATLL). Because CCR4 is expressed on normal regulatory T cells as well as on ATLL cells, MOG may accelerate graft-versus-host disease (GVHD) by eradicating regulatory T cells in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is limited information about its safety and efficacy in patients treated with MOG before allo-HSCT. In the present study, 25 patients with ATLL were treated with MOG before allo-HSCT, after which 18 patients (72%) achieved remission. The overall survival and progression-free survival at 1 year post-transplantation were 20.2% (95% CI, 6.0% to 40.3%) and 15.0% (95% CI, 4.3% to 32.0%), respectively. The cumulative incidence of acute GVHD was 64.0% (95% CI, 40.7% to 80.1%) for grade II-IV and 34.7% (95% CI, 15.8% to 54.4%) for grade III-IV. The cumulative incidence of transplantation-related mortality (TRM) was 49.0% (95% CI, 27.0% to 67.8%). Six of 7 patients with acute GVHD grade III-IV died from GVHD, which was the leading cause of death. In particular, a shorter interval from the last administration of MOG to allo-HSCT was associated with more severe GVHD. MOG use before allo-HSCT may decrease the ATLL burden; however, it is associated with an increase in TRM due to severe GVHD. Because MOG is a potent anti-ATLL agent, new treatment protocols should be developed to integrate MOG at suitable doses and timing of administration to minimize unwanted GVHD development.

Umbilical cord blood transplantation with a reduced-intensity conditioning regimen (RIC-UCBT) is used increasingly in patients who have comorbid organ functions and lack human leukocyte antigen-identical donors. We compared the outcomes in 35 patients who received mycophenolate mofetil plus cyclosporine (MMF/CSP, n = 17) or MMF plus tacrolimus (MMF/TAC, n = 18) for graft-versus-host disease (GVHD) prophylaxis after RIC-UCBT. Cumulative incidence of neutrophil engraftment was 94 and 89 % in MMF/CSP and MMF/TAC groups, respectively (p = 0.34). The incidence of pre-engraftment immune reaction did not differ between the MMF/CSP (41 %) and MMF/TAC (39 %, p = 1.00) groups; however, patients in the MMF/TAC group tended to have a lower incidence of grade II–IV acute GVHD than those in MMF/CSP group (28 vs 53 %, p = 0.11). Overall survival (OS) at 1 year was 43 and 60 % in MMF/CSP and MMF/TAC groups, respectively (p = 0.39). Progression-free survival, non-relapse mortality, and relapse rate were comparable between the two groups (p = 0.76, 0.59, and 0.88, respectively). In multivariate analyses, MMF/TAC GVHD prophylaxis was closely associated with improved OS, but not with incidence of engraftment and acute GVHD. These results suggest that more intensive GVHD prophylaxis with MMF/TAC decreased acute GVHD without affecting other clinical outcomes, resulting in improved OS after RIC-UCBT.