Shigeo Fuji

Double-Expressor Lymphoma Is Associated with Poor Outcomes after Allogeneic Hematopoietic Cell Transplantation

Double-expressor lymphoma (DEL) is a diffuse large B cell lymphoma that exhibits co-expression of MYC and BCL2 proteins by immunohistochemistry. Patients with double-expressor lymphoma have a poor prognosis after standard chemoimmunotherapy or after high-dose chemotherapy with autologous transplantation, but the prognostic impact of DEL after allogeneic hematopoietic cell transplantation has not been well characterized. We retrospectively analyzed 60 consecutive patients with de novo diffuse large B cell lymphoma or transformed follicular lymphoma who underwent allogeneic transplantation at our center and had available immunohistochemistry data. Thirty-seven patients (62%) had DEL. The 2-year progression-free and overall survival rates were lower in patients with DEL than in those without DEL (20% versus 78%; overall P <.001 and 46% versus 77%; overall P = .016, respectively). The cumulative incidence of disease progression at 2 years was higher in patients with DEL (60% versus 13%; overall P = .005). The cumulative incidence of nonrelapse mortality did not differ statistically in the 2 groups. Even in patients with DEL and chemosensitive disease at transplantation, the 2-year progression-free survival rate was only 27% due to early disease progression. Multivariate analysis showed associations between DEL and increased risks of progression-free survival events (hazard ratio [HR], 4.58; 95% confidence interval [CI], 2.07-10.2; P <.001), overall mortality (HR, 2.29; 95% CI, 1.03-5.09; P = .042) and disease progression (HR, 3.60; 95% CI, 1.38-9.44; P = .009). Patients with DEL had poor outcomes after allogeneic transplantation. Innovative strategies are needed to improve outcomes in this population.

Role of up-front allogeneic hematopoietic stem cell transplantation for patients with aggressive adult T-cell leukemia-lymphoma: a decision analysis

Adult T-cell leukemia-lymphoma (ATL) is a distinct peripheral T-cell lymphoma caused by human T-cell lymphotropic virus type I with a dismal outcome [1–4]. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a promising treatment option for patients with aggressive ATL [3, 5]. However, there is still no consensus whether all patients with aggressive ATL should undergo an up-front allo-HSCT. Although retrospective analyses suggested the presence of survival benefit of up-front allo-HSCT compared with chemotherapy alone in patients with intermediateor high-risk ATL [3], presence of significant selection bias made it difficult to assess the equipoise of the two treatments. A prospective randomized clinical trial (RCT) is desirable to clarify the benefit of up-front alloHSCT, but it has never been conducted. In order to address this problem, we here undertook a decision analysis using database the database of 1792 patients with aggressive ATL [3, 6]. Decision analysis is a computerized modeling analysis that can simulate the clinical outcomes of different therapeutic strategies and identify an appropriate therapeutic strategy. This study was approved by the institutional review board of the National Cancer Center, Tokyo, Japan (No. 2014–179). Patients were stratified into the low-, intermediate-, and high-risk groups according to the modified ATL-prognostic index using the prognostic factors, including disease type (acute type), poor performance status, high soluble interleukin-2 receptor level (> 5000 U/mL), high adjusted calcium level ( ≥ 12 mg/dL), and high C-reactive protein level ( ≥ 2.5 mg/dL) [3]. We constructed a Markov decision analysis model to compare the outcomes in two therapeutic strategies: chemotherapy followed by up-front allo-HSCT and chemotherapy alone. As shown in Fig. 1a and Supplemental Fig. 1, all patients were in one of the Markov health states within the model: (1) alive without progressive disease (PD) before HSCT, (2) alive after HSCT before PD, (3) alive

Outcomes of patients with relapsed aggressive adult T-cell leukemia-lymphoma: clinical effectiveness of anti-CCR4 antibody and allogeneic hematopoietic stem cell transplantation

Adult T-cell leukemia-lymphoma (ATL) is a distinct type of peripheral T-cell lymphoma (PTCL) caused by human T-cell lymphotropic virus type I with poor outcomes.[1][1] To improve these results, up-front allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered in transplant-

Decision analysis of up-front autologous hematopoietic stem cell transplantation in patients with peripheral T-cell lymphoma

To the Editor, The clinical outcome in patients with peripheral T-cell lymphoma (PTCL) is poor with conventional chemotherapies [1]. Once relapsed, salvage chemotherapy is often ineffective in patients with PTCL [2, 3]. Thus, upfront autologous hematopoietic stem cell transplantation (auto-HSCT) has been often applied in transplant-eligible patients with chemosensitive PTCL. However, there is still controversy about the indication of up-front auto-HSCT because of a lack of prospective randomized clinical trial (RCT). Decision analysis is a computerized modeling technique that can simulate the clinical outcomes of different therapeutic strategies and identify those that are most effective. This approach is useful in various clinical situations in which a prospective RCT is difficult to conduct [4]. Here, we undertook a decision analysis using a Markov model in patients with PTCL to compare the life expectancy (LE) of patients undergoing chemotherapy followed by up-front auto-HSCT to that of patients receiving chemotherapy alone. Detailed information about the methods is available in Supplemental Table 1 and Supplemental Methods online. As summarized in Figure 1 and Supplemental Fig. 1, health states defined for the clinical course included: (1) alive without progressive disease (PD) before auto-HSCT, (2) alive after auto-HSCT without PD, (3) alive after PD before auto-HSCT, and (4) dead. Each health state was mutually exclusive and was assigned a health utility score based on published studies (Supplemental Table 2). In base case analysis, as shown in Table 1, LE with upfront auto-HSCT was higher than that with chemotherapy alone in the low-risk (PIT 0–2) and high-risk (PIT 3–4) groups. The estimated survival curve depicted by TreeAge showed the superiority of up-front auto-HSCT in both the low-risk and high-risk groups as shown in Figure 2a, b, although the 5-year expected overall survival was comparable in the high-risk group. As shown in Table 1, QALE of up-front auto-HSCT was higher than that of chemotherapy alone in both the low-risk and high-risk groups. We also assessed the impact of delayed up-front autoHSCT using one-way sensitivity analysis. When up-front auto-HSCT was planned at 6 months, 74.1% in the PIT 0–2 group and 59.0% in the PIT 3–4 group received upfront auto-HSCT while disease was under control. As shown in Figure 2c, delay in up-front auto-HSCT beyond 6 months after diagnosis was associated with loss of LE in both the low-risk and high-risk groups, suggesting the benefit of earlier up-front auto-HSCT (Fig. 2). The Monte Carlo simulation showed that the probability of superiority of up-front auto-HSCT was 93.4% in the low-riskand 88.8% in the high-risk groups in terms of LE, and 93.1% in the low-riskand 88.4% in the high-risk groups in terms of QALE. The current simulation study using Markov model demonstrated that the treatment approach incorporating upfront auto-HSCT was the optimal treatment strategy in patients with PTCL, in particular in the low-risk group. Given the absence of prospective RCTs to determine the most favorable front-line treatment strategy in patients with * Shigeo Fuji fujishige1231@gmail.com

Beneficial impact of low-dose rabbit anti-thymocyte globulin in unrelated hematopoietic stem cell transplantation: focusing on difference between stem cell sources

Recently, Lee SJ et al. [1] showed that unrelated bone marrow transplantation (uBMT) was favored because patients who underwent BMT had less long-term complications such as chronic graft-versus-host disease (GVHD) than those who underwent unrelated peripheral blood stem cell transplantation (uPBSCT). In order to prevent longterm complications, it is crucial to establish a strategy to effectively prevent severe chronic GVHD after PBSCT without compromising overall survival (OS). Although anti-T lymphocyte globulin (ATG) might be an option to prevent chronic GVHD, there is still controversy regarding the benefit of ATG [2, 3]. The use of high ATG doses can lead to profound depletion of donor-derived T cells, which can increase the risk of viral infection and attenuate graft-vs.-leukemia effects. Since T-cell profiles vary significantly among stem cell sources, the optimal ATG dose might also differ. We previously reported that use of low-dose ATG-Thymoglobulin (ATG-T; median dose, 1.5 mg/kg) was associated with a lower incidence of severe/refractory chronic GVHD and superior GVHD-free, relapse-free survival (GRFS) in unrelated hematopoietic stem cell transplantation (HSCT), and 98% of patients received uBMT in this study [4]. To evaluate the impact of low-dose ATG-T on clinical outcomes in unrelated HSCT including both uBMT and uPBSCT, we performed a single-center, retrospective analysis of 232 patients with hematological disorders who received unrelated HSCT at the National Cancer Center Hospital from 2012 to 2016 (uBMT, n= 199; uPBSCT, n= 33). This study was approved by the Institutional Review Board of the National Cancer Center, Tokyo, Japan. In this cohort, all patients in the ATG-T group received rabbit ATG (Thymoglobulin; Genzyme-Sanofi, Lyon, France). Acute and chronic GVHD and GRFS were defined according to previously published criteria [5–7]. Chronic lung dysfunction was diagnosed with computed tomography and a respiratory function test according to Bacigalupo’s report [8]. The probability of OS and GRFS were calculated using the Kaplan–Meier method, and groups were compared using the log-rank test. The cumulative incidences of NRM, relapse, acute GVHD, chronic GVHD, and viral infection were calculated by Gray’s method. In the competing risk models for GVHD and viral infection, relapse and death before these events were defined as competing risks. In the competing risk models for NRM, relapse was defined as competing risk. The variables that were evaluated in these analysis were as follows: patient age at transplant (age ≥ 40 vs. age< 40), patient gender (male vs. female), ECOG performance status (0–1 vs. 2–4), disease status (CR vs. non-CR), disease risk index (DRI) (low vs. intermediate vs. high vs. very high) [9], hematopoietic cell transplantation-comorbidity index (HCT-CI) score (0 vs. 1–2 vs. ≥3) [10], intensity of the conditioning regimen (myeloablative conditioning [MAC] vs. reduced-intensity conditioning [RIC]), ATG as GVHD prophylaxis (yes vs. no), HLA disparity assessed by allele typing of HLA-A, B, C, and DRB1 in the GVH-direction (none vs. 1 allele vs. * Shigeo Fuji fujishige1231@gmail.com

The putative anti-leukemic effects of anti-thymocyte globulins in patients with CD7-positive acute myeloid leukemia

Polyclonal anti-thymocyte globulins (ATGs) are widely used in allogeneic stem cell transplantation (allo-SCT) for GvHD prophylaxis. ATGs exerted anti-tumor effects in in vitro experiments, but in vivo studies are lacking. We experienced a case of relapsed AML with cells positive for CD7 who underwent haploidentical SCT and unexpectedly achieved a significant reduction of AML cells in the peripheral blood after receiving ATGs before the administration of other drugs in the conditioning regimen. This patient achieved long-term survival after haploidentical SCT. To assess the impact of ATGs on clinical outcomes in patients with AML, we performed a retrospective analysis of allo-SCT for relapsed/refractory AML and divided 132 patients into four groups according to the expression of CD7 in AML cells and use of ATGs as part of the conditioning regimen, as follows: CD7-positive ATG group (n = 15), CD7-positive no-ATG group (n = 32), CD7-negative ATG group (n = 19), and CD7-negative no-ATG group (n = 66). The overall survival rates in the CD7-positive ATG group were significantly higher than those in the CD7-positive no-ATG group, whereas these rates did not differ statistically between the CD7-negative ATG and CD7-negative no-ATG groups. Our results indicate a possible anti-leukemic effect of ATGs against CD7-positive AML in humans.

Impact of pretransplant central nervous system invasion in patients with aggressive adult T-cell leukemia lymphoma

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

Safety of mogamulizumab for relapsed ATL after allogeneic hematopoietic cell transplantation

Adult T-cell leukemia-lymphoma (ATL) is a peripheral T cell neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1) infection. Although antiviral therapy (such as Zidovudine plus interferon alpha) or combination chemotherapies are used for the treatment of patients with aggressive ATL (acute and lymphoma types), the prognosis of these patients is still very poor [1, 2]. On the other hand, some allogeneic hematopoietic cell transplantation (alloHCT) recipients with aggressive ATL have achieved longterm survival, suggesting the presence of graft-versus-ATL effects after allo-HCT [3]. However, relapse after allo-HCT is still a major obstacle to cure in recipients of allo-HCT [4]. Mogamulizumab (Mog), an anti CC chemokine receptor 4 (CCR4) antibody, was developed for use in patients with aggressive ATL, and previous studies showed that Mog was safe and effective in this population [5]. However, CCR4 is also highly expressed by regulatory T cells (Tregs), which play pivotal roles in the reconstitution of immune tolerance after allo-HCT [6]. Therefore, a major concern is that administration of Mog before or after allo-HCT could potentially increase the risk of graft-versus-host disease (GVHD) by depletion of Tregs. We previously reported that the use of Mog before allo-HCT increased severe acute GVHD and non-relapse mortality (NRM) [7, 8]. However, it remains unknown whether administration of Mog after allo-HCT increases the risk of subsequent GVHD. Hence, we conducted a retrospective analysis of the safety and efficacy of Mog in patients with relapsed aggressive ATL after allo-HCT. We analyzed the clinical data of six patients with aggressive ATL who received Mog for relapsed ATL after allo-HCT at Kumamoto University Hospital from 2014 to 2017. In five of the six patients, we analyzed ATL cells, Tregs and human leukocyte antigen (HLA) in peripheral blood (PB) by multi-color flow cytometry (FCM). Peripheral blood mononuclear cells (PBMCs) were separated by Ficoll-Paque Plus (GE Healthcare), then stained with the following fluorescent-labeled antibodies: APC-CD3 (clone HIT3a), Brilliant Violet 510-CD4 (clone OKT4), APC-Cy7CD25 (clone BC96), Brilliant Violet 421-CD127 (clone A019D5), PE-Cy7-CCR4 (clone 2G12), PE-HLA-A2 (clone BB7.2) (BioLegend) and FITC-HLA-A9 (clone REA127) (Miltenyi Biotec). Flow cytometric analysis was performed using a BD FACSVerse flow cytometer (BD Biosciences). The patient and transplantation characteristics are shown in Table 1. The median time from allo-HCT to relapse was 79 days (range, 56–168 days). The types of relapse were systemic lymphadenopathy without ATL cells in PB in patients 1, 2 and 6, systemic lymphadenopathy with ATL cells in PB in patient 3 and 5 and focal lymphadenopathy with ATL cells in PB in patient 4. The median time from allo-HCT to the administration of Mog was 97 days (range, 83–295 days). In 3 patients (patients 3, 4 and 5), ATL cells in PB promptly disappeared after Mog administration. Meanwhile, in five patients with systemic lymphadenopathy, lymph node lesions grew larger or new lesions appeared even after Mog administration. Patients 1 and 3 died soon after the final administration of Mog due to PD, however, patient 2, 5 and 6 derived some benefit from the combination chemotherapies or radiotherapy after Mog administration. Patient 4 received radiotherapy for focal lymph node lesions before the administration of Mog. Thereafter, she achieved a * Yoshitaka Inoue yinoue1110@gmail.com

Characterization of Late Acute and Chronic Graft-Versus-Host Disease according to the 2014 National Institutes of Health Consensus Criteria in Japanese Patients

To characterize the incidences and outcomes of late acute (LA) and chronic graft-versus-host disease (GVHD) in East Asians according to the 2014 National Institutes of Health criteria, we retrospectively analyzed 506 consecutive Japanese patients who had a first allogeneic hematopoietic cell transplantation (HCT) at our center between 2006 and 2013. According to manifestations at onset 91 patients (60%) had LA GVHD and 60 (40%) had chronic GVHD. The cumulative incidences of LA and chronic GVHD were 20% and 17%, respectively, at 48 months after HCT. The involved sites at the onset of LA GVHD included the skin (71%), gut (13%), and liver (8%). The cumulative incidences of relapse, nonrelapse mortality (NRM), transition to chronic GVHD, and discontinued systemic treatment were 11%, 6%, 22%, and 46%, respectively, at 48 months after onset of LA GVHD. Cox models showed that prior acute GVHD was associated with NRM, and HCT from a female donor to a male patient, myeloablative conditioning, and low Karnofsky performance status were associated with a longer duration of systemic treatment after LA GVHD. The most frequently involved sites at the onset of chronic GVHD included the mouth (83%), liver (75%), skin (69%), and eyes (62%). Cox models showed that use of antithymocyte globulin in conditioning regimens was associated with a higher risk of discontinued systemic treatment after the onset of chronic GVHD. The cumulative incidences of relapse, NRM, and discontinued systemic treatment were 16%, 11%, and 41%, respectively, at 48 months after the onset of chronic GVHD. Our results suggested several potential differences between Japanese patients and those of other ethnicities. A direct comparison is needed to formally investigate ethnic differences.

Pre- and posttransplant use of mogamulizumab in patients with aggressive adult T-cell leukemia-lymphoma: A statement from key opinion leaders in Japan

Recently, the anti‐CCR4 antibody mogamulizumab (Moga, Kyowa Hakko Kirin Co., Ltd, Tokyo, Japan) was approved as a treatment for CCR4‐positive adult T‐cell leukemia‐lymphoma (ATL) in Japan. We use Moga before or after allogeneic hematopoietic stem cell transplantation (allo‐HSCT) in patients with aggressive ATL. A recent retrospective analysis using a database from a nationwide survey showed that the use of Moga before allo‐HSCT was associated with an increased risk of severe/steroid‐refractory acute GVHD and inferior overall survival. Meanwhile, it was reported that a number of patients with chemotherapy‐refractory ATL achieved disease control with Moga, including those who subsequently underwent allo‐HSCT. To address these issues pertaining to Moga in transplant‐eligible patients with ATL, a key opinion leader (KOL) meeting comprising hematologists and transplant physicians was conducted by Kyowa Hakko Kirin Co., Ltd. in Japan. The goal of this KOL meeting was to design a framework to guide decision‐making on the use of Moga in transplant‐eligible patients with ATL. KOLs first presented their experiences, and after a subsequent discussion, the KOLs agreed on the key scientific statement as summarized in this Expert Commentary. Our experiences suggest that a good number of patients benefited from Moga, achieving disease control that was often unattainable by conventional chemotherapies. However, as our statement is based largely on retrospective studies and real clinical practice, it requires further validation. Nevertheless, we believe that this statement should help efficiently guide decision‐making concerning Moga use in transplant‐eligible patients with ATL.