Upfront allo-HSCT after intensive chemotherapy for untreated aggressive ATL: A single arm, phase 3 trial, JCOG0907

Upfront allo-HSCT after intensive chemotherapy for untreated aggressive ATL: A single arm, phase 3 trial, JCOG0907 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Upfront allo-HSCT after intensive chemotherapy for untreated aggressive ATL: A single arm, phase 3 trial, JCOG0907 Takuya Fukushima, Kunihiro Tsukasaki, Ryunosuke Machida, Shinichi Makita, and 22 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8095067/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract This single-arm, phase 3 trial by the Japan Clinical Oncology Group evaluated the strategy of upfront allogeneic hematopoietic stem cell transplantation (allo-HSCT) after intensive chemotherapy for untreated aggressive adult T-cell leukemia-lymphoma (ATL). Patients ≤ 65 years old with aggressive ATL were eligible. The protocol-treatment was VCAP-AMP-VECP as induction-chemotherapy followed by allo-HSCT in first remission. Between 2010 and 2020, 110 patients were enrolled. Among all 92 transplantations, 41 under per-protocol (study transplantation) and 51 under off-protocol received allo-HSCT. The primary endpoint was met with 3-year OS of 44.0% (90% CI, 36.0–51.6 > 25.0). The median survival time of the study transplantation and all transplantation was 3.0 (95% CI, 1.5–5.8) and 2.5 years (95% CI, 1.4–4.8), respectively. Multivariable analysis with a time-dependent covariate for transplantation revealed that the hazard ratio for OS of study transplantation was 0.915 (95% CI, 0.554–1.512). In study transplantation, the rate of treatment-related death (TRD) in related and unrelated transplantation was 16.7% and 20.7%, respectively. Thirty-four deaths due to disease progression (PD) were observed. Upfront allo-HSCT can be recommended for aggressive ATL despite a relatively high rate of PD and TRD. However, the survival benefit of study transplantation remains unclear considering the immortal bias. Health sciences/Medical research/Clinical trial design/Clinical trials/Phase III trials Health sciences/Diseases Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy associated with human T-cell leukemia virus type I (HTLV-1) [ 1 – 5 ]. Countermeasures for HTLV-1, which is endemic in several regions including Japan, aim to address related diseases such as ATL, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), HTLV-1-associated uveitis, and HTLV-1-associated infective dermatitis. These measures have been a significant public health concern for the WHO [ 6 ]. ATL, the most common HTLV-1-associated disease, typically develops 4–7 decades after infection through breastfeeding. ATL is divided into four subtypes: acute, lymphoma, chronic, and smoldering types [ 7 ]. The acute, lymphoma, and unfavourable chronic types—with at least one abnormal value such as high blood urea nitrogen, high lactate dehydrogenase, or low albumin (unfavourable chronic)—are classified as aggressive ATL [ 8 ]. The standard treatments for aggressive ATL are multi-drug chemotherapy with or without mogamulizumab, or antiviral therapy using interferon and zidovudine except in Japan [ 9 – 11 ]. However, the prognosis is extremely poor, with a median survival time (MST) of approximately 1 year [ 12 ]. The Lymphoma Study Group of Japan Clinical Oncology Group (JCOG-LSG) has conducted three clinical trials (JCOG9109 [ 13 ], JCOG9303 [ 14 ], JCOG9801 [ 12 ]) exclusively for patients with untreated aggressive ATL. In the JCOG9801 randomised phase 3 trial with a dose-intensified regimen, VCAP-AMP-VECP, consisting of doxorubicin (DXR), vincristine (VCR), cyclophosphamide (CPA), ranimustine, etoposide, vindesine, carboplatin and prednisolone (PSL), was compared with CHOP-14, which consists of DXR, VCR, CPA and PSL. Both regimens were supported with granulocyte-colony stimulating factor and intrathecal prophylaxis. The VCAP-AMP-VECP regimen showed more effective results despite higher toxicity and is considered one of the standard regimens for patients with untreated aggressive ATL. Nevertheless, the MST of 13 months was not satisfactory. Furthermore, an integrated analysis of 276 patients with aggressive ATL (JCOG0902A), who were enrolled in all three JCOG trials, showed that the 10-year overall survival (OS) was only 16.7% [ 15 ]. Since the 1990s, allogeneic haematopoietic stem cell transplantation (allo-HSCT) has been proactively applied to treat selected patients with aggressive ATL, with some successful cases being reported [ 16 ]. The relatively high graft-versus-HTLV-1/ATL effect may contribute to the promising results [ 17 ]. A nationwide retrospective study of 386 patients with aggressive ATL who underwent allo-HSCT in Japan demonstrated that allo-HSCT using HLA-matched related and unrelated graft sources provided promising long-term survival, with a 3-year OS rate of approximately 40%. However, the 3-year treatment-related death (TRD) rate was equal to or higher than the 3-year OS rate [ 18 ]. We conducted a single-arm, phase 3 trial, JCOG0907, to confirm the efficacy of allo-HSCT as a standard treatment for aggressive ATL. METHODS Study Design This confirmatory single-arm phase 3 trial, JCOG0907, confirmed the efficacy of the treatment strategy of upfront allo-HSCT for untreated patients with aggressive ATL. This JCOG-LSG trial enrolled patients from 30 institutions. The study protocol and informed consent documents were approved by both the JCOG Protocol Review Committee and the institutional review board of each participating institution. Patients Previously untreated patients with aggressive ATL were eligible. The diagnosis of ATL was based on seropositivity for anti-HTLV-1 antibody and histologically and/or cytologically proven peripheral T-cell malignancy. The ATL subtype was determined using the JCOG classification [ 7 ]. The response was judged in accordance with modified response criteria for ATL, adopting the best response from an international consensus meeting [ 10 ]. Each institution judged the diagnosis, subtype, and response, without central review of histological/cytological specimens. Eligibility criteria included no prior chemotherapy or radiotherapy, preserved organ functions, no central nervous system involvement, and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–3. When the trial began in September 2010, JCOG0907 was restricted to myeloablative allo-HSCT (MAST) for patients of ≤ 55 years of age. Due to slow trial accrual and advances in reduced intensity allo-HSCT (RIST) for older patients, the protocol was amended in September 2014 to allow RIST for patients of 56–65 years of age [ 19 ]. Procedure The first-line chemotherapy was VCAP-AMP-VECP based on the phase 3 JCOG9801 trial, which reported a 3-year OS rate of 24% for this regimen. The details of the regimen were described previously [ 12 ], and it was repeated up to 6 cycles. The combination of mogamulizumab with VCAP-AMP-VECP was allowed from September 2014 to April 2016 based on the results of a randomised phase 2 study [ 20 ], but the use of mogamulizumab was later prohibited because of its negative impact on survival for patients with aggressive ATL who received allo-HSCT [ 21 ]. For patients who responded to chemotherapy and had an HLA-matched or 1 locus mismatched sibling donor, or an HLA-matched unrelated (UR) donor, allo-HSCT was performed as early as possible. This trial did not adopt cord blood transplantation (CBT) as protocol transplantation because CBT was identified as a poor prognostic factor for allo-HSCT in aggressive ATL in the Japanese nationwide retrospective study [ 18 ]. Myeloablative conditioning was adapted for patients aged 20–49 years, or for patients aged 50–55 years with less than 2.0 mg/dL of creatinine (Cr) levels and no documented infection. Reduced intensity conditioning was adapted for patients aged 50–55 years with Cr levels of 2.0–3.0 mg/dL or documented infection, and for patients of 56–65 years of age. The myeloablative conditioning regimens basically consisted of busulfan (BU) 0.8 mg/kg 4 times/day or 3.2 mg/kg 1 time/day on days − 7 to − 4 and CPA 60 mg/kg/day on days − 3 and − 2 for related transplantation, or fractionated total body irradiation (TBI) totalling 12 Gray (Gy) on days − 6 to − 4 and CPA 60 mg/kg/day on days − 3 and − 2 for UR transplantation. The reduced intensity conditioning regimens basically consisted of fludarabine (FLU) 30 mg/m 2 /day on days − 8 to − 3 and BU 0.8 mg/kg 4 times/day or 3.2 mg/kg 1 time/day on days − 6 and − 5 for related transplantation, or FLU/BU/ TBI 2 Gy for UR transplantation. The prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporin (CyA) at a dose of 3 mg/kg administered as a continuous intravenous infusion daily from day − 1 and methotrexate (MTX) 15 mg/m 2 on day 1 and 10 mg/m 2 on days 3, 6, and 11 for related myeloablative allo-HSCT (MAST), tacrolimus (TAC) 0.03 mg/kg/day from day − 1 and MTX as previously described for UR MAST, CyA 3 mg/kg/day from day − 1 for related reduced intensity allo-HSCT (RIST), or TAC 0.03 mg/kg/day from day − 1 and MTX 10 mg/m 2 on day 1 and 7 mg/m 2 on days 3 and 6 for UR RIST. Endpoints The primary endpoint was 3-year OS of all enrolled patients. OS was defined as the time from the date of enrolment to death from any cause. Secondary endpoints included OS time, 3-year OS based on acquisition or no acquisition of a donor in accordance with study regulations (acquisition of protocol donor group/no acquisition of protocol donor group), 3-year OS according to study transplantation group/no study transplantation group, 3-year OS according to all transplantation group/no transplantation group, 3-year OS in other subgroups (MAST group, RIST group, all MAST group, all RIST group), adverse events, and TRD. The no study transplantation group consisted of patients who received off-protocol transplantation group and those who did not receive allo-HSCT. Adverse events and laboratory abnormalities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, ver. 3.0. The JCOG Data Center collected and managed case report forms. After going off-protocol due to progression/relapse or transition to off-protocol transplantation, information was collected only about the presence or absence of relapse, post-study treatment, secondary malignancy, and survival outcomes excluding toxicities. In-house data monitoring was performed twice a year by the investigators, as well by the data managers and biostatisticians of JCOG. Statistical Analysis This study aimed to confirm whether the strategy of upfront allo-HSCT after intensive chemotherapy for untreated aggressive ATL is more effective than chemotherapy alone, in terms of the primary endpoint of 3-year OS. At the beginning of the trial, the planned sample size was set at 130, with an expected 3-year OS of 46%, a threshold of 35%, a one-sided alpha of 5%, and a power of 80%. The threshold was determined based on the subgroup analysis of patients of ≤ 55 years of age in the VCAP-AMP-VECP arm of JCOG9801. During the trial, since the protocol was amended to allow RIST for patients of 56–65 years of age, the threshold 3-year OS and expected 3-year OS were changed from 35% to 25% and from 46% to 36%, respectively. Based on these settings, the planned sample size was finally set at 110 patients. The accrual period was changed from 5 years to 10.5 years. The primary analysis was conducted 3 years after the completion of enrolment. In the primary analysis, 3-year OS and its confidence interval (CI) were estimated using the Kaplan–Meier method and the Greenwood formula. If the lower limit of the 90% CI for 3-year OS exceeds the threshold of 25%, we conclude that the protocol treatment of this study is effective, considering (1) the generalisability of the results, (2) the superiority of transplantation over chemotherapy alone, and (3) the balance between costs, adverse reactions, and efficacy of transplantation. For the analysis for (2), to account for immortal time bias, multivariable Cox regression including transplantation as a time-dependent covariate was performed, adjusting for age (< 60 years/≥ 60 years) and PS (0/≥ 1) at baseline. In this study, no interim analysis for efficacy was planned. However, if TRD exceeded 10% in the first-line chemotherapy, 30% in related transplantation, or 35% in unrelated transplantation, these conditions would necessitate the suspension of the study and consideration of its continuation by the Data and Safety Monitoring Committee of JCOG. All statistical analysis were performed using SAS ver. 9.4 (SAS Institute, Cary, NC). RESULTS Patients and Treatment Between September 2, 2010 and June 19, 2020, 111 patients were enrolled. However, 1 patient’s data were excluded due to a violation of the inclusion criteria, as there was no documented informed consent and it was not possible to regain informed consent. Finally, a total of 110 enrolled patients were analysed. The characteristics are listed in Table 1 . One patient's diagnosis was changed to Hodgkin lymphoma (HL) from lymphoma type ATL after careful pathological re-evaluation in their own institution following enrolment. Table 1 Patient characteristics Median age, years (range) 55 (33–65) Sex, male/female 54/56 ECOG PS 0 56 1 49 2 3 3 2 Subtype Acute 72 Lymphoma 27 Unfavourable chronic 9 Favourable chronic 1 Other 1 (Hodgkin lymphoma) JCOG-PI 15 Moderate risk 91 High risk 19 Table 2 Haematologic and non-haematologic toxicities in 42 patients who received transplantation (41 and 1 patients who received study transplantation and post-study transplantation, respectively) Toxicity grade % of patients (n) Neutropenia 4 95.2 (40) Thrombocytopenia 4 92.9 (39) T-bilirubin 3 7.1 (3) AST 3 + 4 19.0 (8) ALT 3 + 4 21.4 (9) γ-GTP 3 38.1 (16) Erythema 3 14.3 (6) Appetite loss 3 33.3 (14) Mucositis 3 35.7 (15) Nausea 3 16.7 (7) Vomiting 3 7.1 (3) Diarrhoea 3 21.4 (9) Haemorrhagic cystitis 3 2.4 (1) Neutropenic fever with G3–4 neutropenia 3 57.1 (24) Pneumonitis 3 4.8 (2) Treatment-related death n = 9 The patient flow diagram is shown in Fig. 1 . Among all 110 enrolled patients, 5 were found to be ineligible after enrolment (favourable chronic type ATL, n = 1; inappropriate organ function, n = 1; complication of another cancer, n = 1; HL, n = 1; no documented informed consent left that was relieved with regaining written IC: n = 1. All 110 enrolled patients received first-line chemotherapy. Among those, 3 patients received VCAP-AMP-VECP combined with mogamulizumab as the protocol treatment. Among these 3 patients, 2 in off-protocol transplantation group died due to TRD, and 1 in no transplantation group died due to PD. Of the 110 patients, 49 (45%) acquired a donor according to study regulations (acquisition of protocol donor group); of these, 41 received per-protocol allo-HSCT (study transplantation group). The details of the study transplantation group are as follows: 19 underwent MAST and 22 underwent RIST according to the conditioning regimen, while 12 had related donors and 29 had unrelated donors. Meanwhile, among 69 patients (no study transplantation group), which included 61 who did not acquire a protocol donor and 8 who did not achieve study transplantation despite acquiring a protocol donor (progressive disease [PD] during preparation for transplantation, n = 4; non-regulated transplantation procedure, n = 2; suspension of harvest due to health problem of donor, n = 1; transfer to a non-participant institute, n = 1), 51 patients received off-protocol transplantation. The details of those 51 patients are as follows: 35 underwent transplantation during first remission/stable disease and 16 underwent transplantation after progression/relapse according to disease status, 11 received MAST and 40 received RIST according to the conditioning regimen, and 11 had related, 15 had unrelated, and 25 had cord blood (CB) donors. Finally, a total of 92 patients received allo-HSCT of various types (Fig. 1 ). Efficacy The median follow-up period of all 110 enrolled patients was 22.0 months (IQR, 10.2–54.6). The trial met the primary endpoint of 3-year OS of 44.0% (90% CI, 36.0–51.6), exceeding the predefined threshold of 25% (Fig. 2 ). With respect to the secondary endpoint, the median survival times (MST) for the acquisition of protocol donor group (n = 49) and no acquisition of protocol donor group (n = 61) were 3.4 years (95% CI, 1.6–6.9) and 1.2 years (95% CI, 0.9–4.3), respectively (Supplement Figure S1 ). The MST for the study transplantation group (n = 41) and no study transplantation group (n = 69) were 3.0 years (95% CI, 1.5–5.8) and 1.3 years (95% CI, 0.9–4.6), respectively. The MST for the all transplantation group (n = 92) and no transplantation group (n = 18) was 2.5 years (95% CI, 1.4–4.8) and 0.9 years (95% CI, 0.4–1.2), respectively. Among all 92 transplantation patients, the MST for related, unrelated, and cord blood (CB) transplantation showed no significant difference, with 2.4 years (95% CI, 1.1 to not estimable), 3.4 years (95% CI, 1.5–6.9), and 1.4 years (95% CI, 0.9–10.5), respectively (Supplement Figure S2). Figure 3 A shows the timing of transplantation and survival. The median time from diagnosis to transplantation was similar in the study transplantation group and the group that received off-protocol transplantation. Allo-HSCT potentially has an immortal time bias because only patients who survive through chemotherapy can achieve allo-HSCT. To reduce this bias, we performed a multivariable analysis, using a time-dependent covariate for the presence or absence of transplantation. Univariable analysis revealed that the hazard ratio (HR) for OS of the study transplantation group (n = 41) relative to the no study transplantation group (n = 69) was 0.944 (95% CI, 0.575–1.549). Multivariable analysis showed that the HR for OS of the study transplantation group relative to the no study transplantation group was 0.915 (95% CI, 0.554–1.512) (Fig. 3 B). Univariable analysis revealed that the HR for OS of the all transplantation group (n = 92) relative to the no transplantation group (n = 18) was 0.882 (95% CI, 0.437–1.780). Multivariable analysis showed that the HR for OS of the all transplantation group relative to the no transplantation group was 0.896 (95% CI, 0.446–1.800) (Fig. 3 C). In further analysis, univariable analysis revealed that the HR for OS of the upfront setting transplantation group (excluding transplantation after progression/relapse, n = 76; study transplantation, n = 41; off-protocol transplantation, n = 35) relative to the no transplantation group (n = 18) was 0.635 (95% CI, 0.317–1.275). Multivariable analysis showed that the HR for OS of the upfront setting transplantation group relative to the no transplantation group was 0.654 (95% CI, 0.326–1.311) (Fig. 3 D). Safety In this trial, there was no TRD during chemotherapy. Among the 41 patients in the study transplantation group, TRD in related transplantation and unrelated transplantation were 16.7% (related transplantation, n = 2/12) and 20.7% (unrelated transplantation, n = 6/29), respectively. Among 42 patients (study transplantation, n = 41; CBT after completion of conditioning regimen as study treatment, n = 1) who received allo-HSCT and had available data for toxicities, grade 4 neutropenia was observed in 95.2% (n = 40/42), and grade 4 thrombocytopenia in 92.9% (n = 39/42). Grade 3–4 elevation of total bilirubin, AST, ALT, and γ-GTP were observed in 7.1% (n = 3/42), 19.0% (n = 8/42), 21.4% (n = 9/42), and 38.1% (n = 16/42), respectively. Adverse events associated with GVHD included grade 3–4 skin rash in 14.3% (n = 6/42), diarrhoea in 21.4% (n = 9/42), and pneumonitis in 4.8% (n = 2/42). Causes of death for all 70 patients included ATL (n = 34), TRD due to study transplantation (n = 9), TRD due to post-study treatment (n = 21), and other diseases (n = 6; lung cancer, myelodysplastic syndrome, cerebral haemorrhage, acute myeloid leukemia, aspiration pneumonia, coronavirus disease 2019 pneumonia). DISCUSSION This is the first well-designed and confirmatory single-arm, phase 3 trial on the treatment strategy of upfront allo-HSCT after intensive chemotherapy for patients with untreated aggressive ATL. Conducting a randomised controlled trial for the presence or absence of allo-HSCT is extremely difficult as only some selected patients with suitable donors can receive it. This trial met the primary endpoint, with the lower limit of the 90% CI for 3-year OS (36.0%) exceeding the threshold of 25% set by JCOG9801 [ 12 ]. Allo-HSCT potentially has an immortal time bias, as only patients who survive prior chemotherapy can receive it. To evaluate this issue, we performed a multivariable analysis with a time-dependent covariate in addition to the primary endpoint. The HR in OS of the study transplantation group relative to the no study transplantation group was 0.915 (95% CI, 0.554–1.512), suggesting there is no survival benefit of study transplantation. On the other hand, the HR in OS of the upfront transplantation group (n = 76 patients [study transplantation, n = 41; off-protocol transplantation during remission/stable disease status, n = 35) relative to the no transplantation group (n = 18) was 0.654 (95% CI, 0.326–1.311), suggesting that upfront allo-HSCT has better survival outcomes. However, it is important to note that the patient population who received transplantation in their first remission/stable disease may be in a relatively better condition, and that patients who underwent a transplantation after progression/relapse—and who potentially had a poor prognosis—were excluded. Consequently, these data indicate that the survival benefit of study transplantation in this trial for patients with aggressive ATL remains unclear. This trial initially started using only MAST for patients of ≤ 55 years of age as study transplantation from September 2010. However, some promising results regarding RIST for older patients with aggressive ATL have been reported [ 19 , 22 , 23 ], and the protocol was amended to incorporate RIST and expand the age group to 56–65 years from September 2014. On the other hand, the protocol treatment permitted HLA identical or 1 locus mismatched sibling, or HLA identical unrelated donors excluding CB as eligible donors during the whole study period because CBT was identified as a poor risk factor in the Japanese nationwide retrospective study of allo-HSCT for aggressive ATL [ 18 ]. After the 2010s, the feasibility of CBT for patients with aggressive ATL was demonstrated in some analyses [ 24 , 25 ]. Furthermore, allo-HSCT from HLA-haploidentical related donors has also been attempted for aggressive ATL recently [ 25 , 26 ]. The prospective observational study between 2015 and 2018 in Japan demonstrated that 2-year probabilities of OS of 90 patients who received allo-HSCT (CB, n = 30; HLA-haploidentical related donor, n = 20; other related donor, n = 14; other unrelated donor, n = 26) was 44%, and OS did not differ statistically according to donor type [ 25 ]. In this trial among 51 patients who received off-protocol transplantation, 25 patients (in remission, n = 17; in progression/relapse, n = 8) and 2 patients (in remission, n = 2) received CBT and haploidentical transplantation, respectively. There was no significant difference in MST among related, unrelated, and CB transplantation in 92 patients of the all transplantation group, suggesting the availability of CB as a donor source for allo-HSCT for untreated aggressive ATL. In this trial, the proportions of deaths due to disease progression and TRD were relatively high. The TRD rate of allo-HSCT for patients with aggressive ATL has been reported to be higher relative to other hematologic malignancies [ 16 ]. The Japanese nationwide retrospective study demonstrated that cumulative incidence rates of TRD at 3 years after transplantation in HLA-matched related, HLA-mismatched related, unrelated and CB transplantation, were 37%, 43%, 42%, and 52%, respectively [ 18 ]. In this trial, the TRD rate among 41 patients who received study transplantation was 16.7% (2/12) in related transplantation and 20.7% (6/29) in unrelated transplantation. These were below the prespecified permissible rates of TRD (30% and 35% in related and unrelated transplantation, respectively). The TRD rate in this trial may be underestimated because data from 1 patient (excluded due to lack of informed consent document) who died from transplantation-related complications was eliminated. Additionally, there were no detailed data for patients who received off-protocol transplantation. However, HLA-matched and 1 locus mismatched related, as well as HLA-matched unrelated transplantation, were considered to be tolerable treatment procedures for patients with aggressive ATL in this trial. Disease progression is more common in ATL compared with other aggressive lymphomas, both with chemotherapy alone and with chemotherapy followed by allo-HSCT. Further efforts are needed to improve the prognosis of aggressive ATL. One possibility is adding molecular targeting agents in combination with chemotherapy or as maintenance after allo-HSCT. Several promising new agents for aggressive ATL include mogamulizumab, lenalidomide, tucidinostat, and valemetostat [ 27 – 29 ]. Mogamulizumab should be carefully considered immediately before allo-HSCT and after allo-HSCT due to the potential for worsening GVHD [ 21 ]. However, combining mogamulizumab with chemotherapy has shown promise in prospective and retrospective studies of transplantation ineligible ATL patients [ 30 , 31 ]. Using this agent at the appropriate timing may improve the results of allo-HSCT-containing therapy for aggressive ATL. Secondly, improving allo-HSCT itself, as mentioned above, is essential. Lastly, early intervention is important for better managing relapse before and after allo-HSCT. The limitations of this trial included the enrolment of 51 patients who received off-protocol transplantation and 2 patients with ineligible disease types (favourable chronic ATL and HL). These deviations complicated the evaluation of the study results. Although the trial met its primary endpoint, the survival benefit of study transplantation for patients with aggressive ATL remains unclear. This is due to the immortal time bias suggested by the HR of 0.915 (95% CI, 0.554–1.512) for OS in the study transplantation group (n = 41) compared to the no study transplantation group (n = 69) in a multivariable analysis with a time-dependent covariate for the presence or absence of transplantation. Furthermore, to evaluate the significance of upfront allo-HSCT for patients with aggressive ATL as a basic concept for the treatment strategy of this trial, we calculated the HR for OS of the upfront setting transplantation group (n = 76 [study transplantation, n = 41; off-protocol transplantation, n = 35]) relative to the no transplantation group (n = 18). The HR was 0.654 (95% CI 0.326–1.311) in a multivariable analysis. This result suggests that upfront allo-HSCT could be recommended for chemotherapy-sensitive patients with aggressive ATL. In conclusion, the strategy of upfront allo-HSCT after intensive chemotherapy can be recommended for untreated aggressive ATL, despite the relatively high proportion of disease progression and TRD as causes of death. However, the survival benefit of study transplantation in this trial remains unclear. Declarations Acknowledgments This study was supported in part by the National Cancer Center Research and Development Fund (29-A-3, 2020-J-3, 2023-J-03) from the Ministry of Health, Labour and Welfare of Japan. We thank all the patients and their families, all the study site coordinators and investigators, and the data managers at the JCOG Data Center. Author Contributions Conception and design: T Fukushima, K Tsukasaki, T Shibata, H Fukuda Administrative support: H Nagai Provision of study materials and patients: T Fukushima, K Tsukasaki, D Maruyama, S Makita, S Kusumoto, S Iida, M Tokunaga, Y Miyazaki, M Yoshimitsu, I Choi, K Morichika, K Miyazaki, J Makiyama, K Nosaka, H Katsuya, T Kawakita, Y Minami, S Ota, T Uchida, N Kubota, Y Harada, K Takase Collection and assembly of data: R Machida, T Shibata, H Fukuda Data analysis and interpretation: T Fukushima, K Tsukasaki, R Machida, T Shibata, H Fukuda, H Nagai Manuscript writing: All authors Final approval of manuscript: All authors Accountable for all aspects of the work: All authors AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Takuya Fukushim a Research Funding: Daiichi-Sankyo Honoraria: Meiji Seika Pharma, AstraZeneca, Daiichi-Sankyo, Chugai Pharmaceutical, Bristol Myers Squibb, Kyowa Kirin, Novartis, Amgen. Kunihiro Tsukasaki Research Funding: Kyowa Kirin, Meiji Seika Pharma, Bristol Myers Squibb, Byer, Daiichi-Sankyo Honoraria: Eisai, Takeda, Meiji Seika Pharma, Sekisui Medical, Daiichi-Sankyo, Nippon-Shinyaku Consulting or Advisory Role: Meiji Seika Pharma, Daiichi-Sankyo. Ryunosuke Machida Shinichi Makita Honoraria: AstraZeneca, BMS, Chugai, Genmab, Gilead, Kyowa Kirin, Novartis, Takeda. Shigeru Kusumoto Research Funding: Daiichi-Sankyo, Bristol Myers Squibb, Chugai, Ono, Genmab, Meiji Seika Pharma, Janssen, Takeda, AbbVie, Shionogi Honoraria: Chugai, Eisai, Janssen, Meiji Seika Pharma, AbbVie, Nippon Shinyaku, Astellas, Novartis, Zenyaku, Fujimoto, Daiichi-Sankyo, SymBio, Ono, Lilly, Genmab, Sanofi, Takeda, Sumitomo, Mundi Pharma, AstraZeneca. Consulting or Advisory Role: Daiichi-Sankyo, Lilly, Chugai, Kyowa Kirin, Genmab, Janssen Shinsuke Iida Research Funding: Pfizer, Bristol Myers Squibb, Janssen, Sanofi, Takeda, Chugai, AstraZeneca, Ono, Shionogi, Glaxo SmithKein, Daiichi-Sankyo, AbbVie, Amgen, Otsuka, Alexion, Novartis Honoraria: Bristol Myers Squibb, Pfizer, Janssen, Sanofi, Takeda, Ono, AstraZeneca. Masahito Tokunaga Honoraria: Meiji Seika Pharma and Minophagen. Yasushi Miyazaki Honoraria: Kyowa Kirin, Chugai, Takeda leadership or fiduciary role in other board, society, committee or advocacy group: Japan Adult Leukemia Study Group. Makoto Yoshimitsu Honoraria: Takeda, Sanofi, Novartis, Chugai, PharmaEssentia, Astellas, Genmab, Ono, Daiichi-Sankyo, Nippon Shinyaku, Bristol Myers Squibb, Eisai, Kissei, Nippon Kayaku, Meiji Seika Pharma Ilseung Choi Kazuho Morichika Kana Miyazaki Research Funding : Takeda, Otsuka, Chugai, Kyowa Kirin, Sumitomo, Zenyaku Kogyo; Honoraria: Chugai, Janssen, AstraZeneca, Novartis, Incyte, Asahi Kasei, Abbvie, SymBio, Ono, Genmab, Meiji Seika Pharma, Bristol Myers Squibb, Kyowa Kirin, Daiichi-Sankyo, Gilead, Nippon Shinyaku Junya Makiyama Honoraria: AbbVie, Chugai, Janssen, Meiji Seika Pharma, Otsuka, Symbio, Bristol Myers Squibb, Daiichi-Sankyo, Kyowa Kirin, Ono, Sanofi, Takeda Kisato Nosaka Research Funding: Kyowa Kirin, Chugai Honoraria: Meiji Seika Pharma, Chugai, Bristol Myers Squibb, Kyowa Kirin, AbbVie, Daiichi-Sankyo, Eisai, Ohara, Janssen, Minophagen Hiroo Katsuya Toshiro Kawakita Yosuke Minami Honoraria: Astellas, Novartis, Daiichi-Sankyo, Pfizer, and Otsuka Consulting or Advisory Role: Takeda, Novartis, CMIC Shuichi Ota Honoraria: Novartis, Takeda, AstraZeneca, AbbVie, ParmaEssentia, Bristol Myers Squibb, Janssen, Amgen, Sanofi Toshiki Uchida Honoraria: Novartis, Janssen, AbbVie, Nippon Shinyaku, Meiji Seika Pharma, Eisai, Chugai, Asahi Kasei, Kissei, Sanofi, Bristol Myers Squibb, Kyowa Kirin, Nippon Kayaku, Takeda Nobuko Kubota Yasuhiko Harada Ken Takase Taro Shibata Haruhiko Fukuda Research Funding: AstraZeneca, Ono, Chugai, Takeda Honoraria: Chugai, Kyowa Kirin, CMIC. Hirokazu Nagai Research Funding: AbbVie, AstraZeneca, Beigene, Genmab, Incyte Biosciences Japan, Janssen, Lilly, Takeda, Kyowa Kirin, MSD, Mitsubishi Tanabe, Chugai, Daiichi-Sankyo, Celgen, Zenyaku Kogyo, Solasia, Ono Regeneron, Haihe Honoraria: AbbVie, AstraZeneca, Genmab, Janssen, Eli Lilly, Takeda, Kyowa Kirin, MSD, Eisai, Novartis, Ono, Dainippon Sumitomo, Chugai, Meiji Seika Pharma, Mundi Pharma, GSK, BMS, Nippon Kayaku, Nippon Shinyaku, Beigene Dai Marumaya Research Funding: Ono, Janssen, Eisai, Chugai, Kyowa Kirin, MSD, Zenyaku, Sanofi, Symbio, Takeda, AbbVie, AstraZeneca, BMS，Genmab Novartis, Otsuka, Taiho, Pfizer, Astellas Honoraria: Ono Nippon Shinyaku, Janssen, Mundipharma, Eisai, Chugai, Kyowa Kirin, MSD, Zenyaku Sanofi, Symbio, Takeda, AbbVie, AstraZeneca, BMS, Genmab, Novartis Consulting or Advisory Role: Janssen, AstraZeneca, Chugai, AbbVie, Genmab, Sanofi, BMS, Pfizer. Data Availability Statement Individual participant data that underlie the results reported in this article, after deidentification will be shared if investigators whose proposed use of the data has been approved by the investigators from Lymphoma Study Group of JCOG identified for this purpose. Proposals should be directed to [email protected] . The data will be available for achieving aims in the approved proposal. CLINICAL TRIAL INFORMATION jRCTs031180243 References Uchiyama T, Sagawa K, Takatsuki K, Uchino H. Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood 1977; 50: 481–492. Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci U S A 1980; 77: 7415–7419. Hinuma Y, Nagata K, Hanaoka M, Nakai M, Matsumoto T, Kinoshita KI, et al. 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An update on the development in the treatment of adult T-cell leukemia-lymphoma: current knowledge and future perspective. Jpn J Clin Oncol 2023; 53: 1104–1111. Maruyama D, Jacobsen E, Porcu P, Allen P, Ishitsuka K, Kusumoto S, et al. Valemetostat monotherapy in patients with relapsed or refractory non-Hodgkin lymphoma: a first-in-human, multicentre, open-label, single-arm, phase 1 study. Lancet Oncol 2024; 25: 1589–1601. Shichijo T, Nosaka K, Tatetus H, Higuchi Y, Endo S, Inoue Y, et al. Beneficial impact of first-line mogamulizumab-containing chemotherapy in adult T-cell leukemia-lymphoma. Br J Haematol 2022; 198: 983–987. Yoshimitsu M, Choi I, Kusumoto S, Shimokawa M, Utsunomiya A, Suehiro Y, et al. A phase 2 trial of CHOP with anti-CCR4 antibody mogamulizumab for elderly patients with adult T-cell leukemia/lymphoma. Blood 2025; 146: 1440–1449. Additional Declarations Yes there is potential conflict of interest. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8095067","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":545194291,"identity":"bcc7005e-ce10-46f3-bd5d-4c4b0ffd323e","order_by":0,"name":"Takuya 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09:20:26","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":23880,"visible":true,"origin":"","legend":"","description":"","filename":"25LEU1884.json","url":"https://assets-eu.researchsquare.com/files/rs-8095067/v1/08cc0f3dcdb0b58494c9e88a.json"},{"id":98753108,"identity":"4f11d054-06f2-4666-9cfb-d02f7798d815","added_by":"auto","created_at":"2025-12-22 09:20:26","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":136051,"visible":true,"origin":"","legend":"","description":"","filename":"JCOG0907Supplementarydata.docx","url":"https://assets-eu.researchsquare.com/files/rs-8095067/v1/7944f8596d64fabe3630dabb.docx"},{"id":98753102,"identity":"6a348044-a37e-40de-a084-034a1b50846a","added_by":"auto","created_at":"2025-12-22 09:20:26","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":54893,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eParticipant flow\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMAST, myeloablative allogeneic hematopoietic stem cell transplantation; RIST, reduced intensity allogeneic hematopoietic stem cell transplantation; R, related; UR, unrelated; CB, cord blood.\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8095067/v1/8164f19f01c60b38e0c11a8c.jpg"},{"id":98753103,"identity":"aac7863a-8afa-4d90-bed3-bfeac97b09c0","added_by":"auto","created_at":"2025-12-22 09:20:26","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":24288,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier estimate of overall survival (OS) for all enrolled patients (n = 110)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCI, confidence interval\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8095067/v1/cd37a899c4d60a65d09528b2.jpg"},{"id":98778357,"identity":"f6090ee5-99bc-4f7e-8a2f-7d1db3972d7c","added_by":"auto","created_at":"2025-12-22 12:29:11","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":42171,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSwimmer plot for timing of transplantation for all enrolled patients (n = 110) (A) and Kaplan–Meier estimate of overall survival (OS) for no study transplantation (n = 69) vs. study transplantation (n = 41) (B), no transplantation (n = 18) vs. all transplantation (n = 92) (C), and no transplantation (n = 18) vs. transplantation in 1st remission (n = 76) vs. transplantation after relapse (n = 16) (D). Hazard ratios (HRs) of upfront transplantation group and transplantation after progression/relapse group to no transplantation group were estimated by a Cox proportional hazards model including (study) transplantation as time-dependent covariate.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOS, overall survival; CI, confidence interval.\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8095067/v1/c2f9459b68df99ec999e3599.jpg"},{"id":98783576,"identity":"41f9e478-5178-4712-be1c-cbcc2d5fe39b","added_by":"auto","created_at":"2025-12-22 12:42:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1628845,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8095067/v1/937bf47a-1d87-4cb7-ad87-491c6689af1e.pdf"},{"id":98778670,"identity":"1d5bfdae-dd14-4c2f-9cfc-417b39ad9572","added_by":"auto","created_at":"2025-12-22 12:29:29","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":136051,"visible":true,"origin":"","legend":"Supplementary data for JCOG0907","description":"","filename":"JCOG0907Supplementarydata.docx","url":"https://assets-eu.researchsquare.com/files/rs-8095067/v1/a532d9ffdbd9e63a456dde7f.docx"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential conflict of interest.","formattedTitle":"Upfront allo-HSCT after intensive chemotherapy for untreated aggressive ATL: A single arm, phase 3 trial, JCOG0907","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eAdult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy associated with human T-cell leukemia virus type I (HTLV-1) [\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Countermeasures for HTLV-1, which is endemic in several regions including Japan, aim to address related diseases such as ATL, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), HTLV-1-associated uveitis, and HTLV-1-associated infective dermatitis. These measures have been a significant public health concern for the WHO [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. ATL, the most common HTLV-1-associated disease, typically develops 4\u0026ndash;7 decades after infection through breastfeeding. ATL is divided into four subtypes: acute, lymphoma, chronic, and smoldering types [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The acute, lymphoma, and unfavourable chronic types\u0026mdash;with at least one abnormal value such as high blood urea nitrogen, high lactate dehydrogenase, or low albumin (unfavourable chronic)\u0026mdash;are classified as aggressive ATL [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe standard treatments for aggressive ATL are multi-drug chemotherapy with or without mogamulizumab, or antiviral therapy using interferon and zidovudine except in Japan [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, the prognosis is extremely poor, with a median survival time (MST) of approximately 1 year [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The Lymphoma Study Group of Japan Clinical Oncology Group (JCOG-LSG) has conducted three clinical trials (JCOG9109 [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], JCOG9303 [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], JCOG9801 [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]) exclusively for patients with untreated aggressive ATL. In the JCOG9801 randomised phase 3 trial with a dose-intensified regimen, VCAP-AMP-VECP, consisting of doxorubicin (DXR), vincristine (VCR), cyclophosphamide (CPA), ranimustine, etoposide, vindesine, carboplatin and prednisolone (PSL), was compared with CHOP-14, which consists of DXR, VCR, CPA and PSL. Both regimens were supported with granulocyte-colony stimulating factor and intrathecal prophylaxis. The VCAP-AMP-VECP regimen showed more effective results despite higher toxicity and is considered one of the standard regimens for patients with untreated aggressive ATL. Nevertheless, the MST of 13 months was not satisfactory. Furthermore, an integrated analysis of 276 patients with aggressive ATL (JCOG0902A), who were enrolled in all three JCOG trials, showed that the 10-year overall survival (OS) was only 16.7% [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSince the 1990s, allogeneic haematopoietic stem cell transplantation (allo-HSCT) has been proactively applied to treat selected patients with aggressive ATL, with some successful cases being reported [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The relatively high graft-versus-HTLV-1/ATL effect may contribute to the promising results [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. A nationwide retrospective study of 386 patients with aggressive ATL who underwent allo-HSCT in Japan demonstrated that allo-HSCT using HLA-matched related and unrelated graft sources provided promising long-term survival, with a 3-year OS rate of approximately 40%. However, the 3-year treatment-related death (TRD) rate was equal to or higher than the 3-year OS rate [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe conducted a single-arm, phase 3 trial, JCOG0907, to confirm the efficacy of allo-HSCT as a standard treatment for aggressive ATL.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eThis confirmatory single-arm phase 3 trial, JCOG0907, confirmed the efficacy of the treatment strategy of upfront allo-HSCT for untreated patients with aggressive ATL. This JCOG-LSG trial enrolled patients from 30 institutions. The study protocol and informed consent documents were approved by both the JCOG Protocol Review Committee and the institutional review board of each participating institution.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePatients\u003c/h3\u003e\n\u003cp\u003ePreviously untreated patients with aggressive ATL were eligible. The diagnosis of ATL was based on seropositivity for anti-HTLV-1 antibody and histologically and/or cytologically proven peripheral T-cell malignancy. The ATL subtype was determined using the JCOG classification [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The response was judged in accordance with modified response criteria for ATL, adopting the best response from an international consensus meeting [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Each institution judged the diagnosis, subtype, and response, without central review of histological/cytological specimens.\u003c/p\u003e \u003cp\u003eEligibility criteria included no prior chemotherapy or radiotherapy, preserved organ functions, no central nervous system involvement, and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0\u0026ndash;3. When the trial began in September 2010, JCOG0907 was restricted to myeloablative allo-HSCT (MAST) for patients of \u0026le;\u0026thinsp;55 years of age. Due to slow trial accrual and advances in reduced intensity allo-HSCT (RIST) for older patients, the protocol was amended in September 2014 to allow RIST for patients of 56\u0026ndash;65 years of age [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eProcedure\u003c/h3\u003e\n\u003cp\u003eThe first-line chemotherapy was VCAP-AMP-VECP based on the phase 3 JCOG9801 trial, which reported a 3-year OS rate of 24% for this regimen. The details of the regimen were described previously [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], and it was repeated up to 6 cycles. The combination of mogamulizumab with VCAP-AMP-VECP was allowed from September 2014 to April 2016 based on the results of a randomised phase 2 study [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], but the use of mogamulizumab was later prohibited because of its negative impact on survival for patients with aggressive ATL who received allo-HSCT [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. For patients who responded to chemotherapy and had an HLA-matched or 1 locus mismatched sibling donor, or an HLA-matched unrelated (UR) donor, allo-HSCT was performed as early as possible. This trial did not adopt cord blood transplantation (CBT) as protocol transplantation because CBT was identified as a poor prognostic factor for allo-HSCT in aggressive ATL in the Japanese nationwide retrospective study [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Myeloablative conditioning was adapted for patients aged 20\u0026ndash;49 years, or for patients aged 50\u0026ndash;55 years with less than 2.0 mg/dL of creatinine (Cr) levels and no documented infection. Reduced intensity conditioning was adapted for patients aged 50\u0026ndash;55 years with Cr levels of 2.0\u0026ndash;3.0 mg/dL or documented infection, and for patients of 56\u0026ndash;65 years of age. The myeloablative conditioning regimens basically consisted of busulfan (BU) 0.8 mg/kg 4 times/day or 3.2 mg/kg 1 time/day on days \u0026minus;\u0026thinsp;7 to \u0026minus;\u0026thinsp;4 and CPA 60 mg/kg/day on days \u0026minus;\u0026thinsp;3 and \u0026minus;\u0026thinsp;2 for related transplantation, or fractionated total body irradiation (TBI) totalling 12 Gray (Gy) on days \u0026minus;\u0026thinsp;6 to \u0026minus;\u0026thinsp;4 and CPA 60 mg/kg/day on days \u0026minus;\u0026thinsp;3 and \u0026minus;\u0026thinsp;2 for UR transplantation. The reduced intensity conditioning regimens basically consisted of fludarabine (FLU) 30 mg/m\u003csup\u003e2\u003c/sup\u003e/day on days \u0026minus;\u0026thinsp;8 to \u0026minus;\u0026thinsp;3 and BU 0.8 mg/kg 4 times/day or 3.2 mg/kg 1 time/day on days \u0026minus;\u0026thinsp;6 and \u0026minus;\u0026thinsp;5 for related transplantation, or FLU/BU/ TBI 2 Gy for UR transplantation. The prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporin (CyA) at a dose of 3 mg/kg administered as a continuous intravenous infusion daily from day \u0026minus;\u0026thinsp;1 and methotrexate (MTX) 15 mg/m\u003csup\u003e2\u003c/sup\u003e on day 1 and 10 mg/m\u003csup\u003e2\u003c/sup\u003e on days 3, 6, and 11 for related myeloablative allo-HSCT (MAST), tacrolimus (TAC) 0.03 mg/kg/day from day \u0026minus;\u0026thinsp;1 and MTX as previously described for UR MAST, CyA 3 mg/kg/day from day \u0026minus;\u0026thinsp;1 for related reduced intensity allo-HSCT (RIST), or TAC 0.03 mg/kg/day from day \u0026minus;\u0026thinsp;1 and MTX 10 mg/m\u003csup\u003e2\u003c/sup\u003e on day 1 and 7 mg/m\u003csup\u003e2\u003c/sup\u003e on days 3 and 6 for UR RIST.\u003c/p\u003e\n\u003ch3\u003eEndpoints\u003c/h3\u003e\n\u003cp\u003eThe primary endpoint was 3-year OS of all enrolled patients. OS was defined as the time from the date of enrolment to death from any cause. Secondary endpoints included OS time, 3-year OS based on acquisition or no acquisition of a donor in accordance with study regulations (acquisition of protocol donor group/no acquisition of protocol donor group), 3-year OS according to study transplantation group/no study transplantation group, 3-year OS according to all transplantation group/no transplantation group, 3-year OS in other subgroups (MAST group, RIST group, all MAST group, all RIST group), adverse events, and TRD. The no study transplantation group consisted of patients who received off-protocol transplantation group and those who did not receive allo-HSCT.\u003c/p\u003e \u003cp\u003eAdverse events and laboratory abnormalities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, ver. 3.0.\u003c/p\u003e \u003cp\u003eThe JCOG Data Center collected and managed case report forms. After going off-protocol due to progression/relapse or transition to off-protocol transplantation, information was collected only about the presence or absence of relapse, post-study treatment, secondary malignancy, and survival outcomes excluding toxicities. In-house data monitoring was performed twice a year by the investigators, as well by the data managers and biostatisticians of JCOG.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eThis study aimed to confirm whether the strategy of upfront allo-HSCT after intensive chemotherapy for untreated aggressive ATL is more effective than chemotherapy alone, in terms of the primary endpoint of 3-year OS. At the beginning of the trial, the planned sample size was set at 130, with an expected 3-year OS of 46%, a threshold of 35%, a one-sided alpha of 5%, and a power of 80%. The threshold was determined based on the subgroup analysis of patients of \u0026le;\u0026thinsp;55 years of age in the VCAP-AMP-VECP arm of JCOG9801. During the trial, since the protocol was amended to allow RIST for patients of 56\u0026ndash;65 years of age, the threshold 3-year OS and expected 3-year OS were changed from 35% to 25% and from 46% to 36%, respectively. Based on these settings, the planned sample size was finally set at 110 patients. The accrual period was changed from 5 years to 10.5 years. The primary analysis was conducted 3 years after the completion of enrolment.\u003c/p\u003e \u003cp\u003eIn the primary analysis, 3-year OS and its confidence interval (CI) were estimated using the Kaplan\u0026ndash;Meier method and the Greenwood formula. If the lower limit of the 90% CI for 3-year OS exceeds the threshold of 25%, we conclude that the protocol treatment of this study is effective, considering (1) the generalisability of the results, (2) the superiority of transplantation over chemotherapy alone, and (3) the balance between costs, adverse reactions, and efficacy of transplantation. For the analysis for (2), to account for immortal time bias, multivariable Cox regression including transplantation as a time-dependent covariate was performed, adjusting for age (\u0026lt;\u0026thinsp;60 years/\u0026ge; 60 years) and PS (0/\u0026ge; 1) at baseline.\u003c/p\u003e \u003cp\u003eIn this study, no interim analysis for efficacy was planned. However, if TRD exceeded 10% in the first-line chemotherapy, 30% in related transplantation, or 35% in unrelated transplantation, these conditions would necessitate the suspension of the study and consideration of its continuation by the Data and Safety Monitoring Committee of JCOG. All statistical analysis were performed using SAS ver. 9.4 (SAS Institute, Cary, NC).\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatients and Treatment\u003c/h2\u003e \u003cp\u003eBetween September 2, 2010 and June 19, 2020, 111 patients were enrolled. However, 1 patient\u0026rsquo;s data were excluded due to a violation of the inclusion criteria, as there was no documented informed consent and it was not possible to regain informed consent. Finally, a total of 110 enrolled patients were analysed. The characteristics are listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. One patient's diagnosis was changed to Hodgkin lymphoma (HL) from lymphoma type ATL after careful pathological re-evaluation in their own institution following enrolment.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMedian age, years (range)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55 (33\u0026ndash;65)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSex, male/female\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54/56\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eECOG PS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSubtype\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAcute\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLymphoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnfavourable chronic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFavourable chronic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (Hodgkin lymphoma)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eJCOG-PI\u003csup\u003e15\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eModerate risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e91\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHigh risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eHaematologic and non-haematologic toxicities in 42 patients who received transplantation\u003c/b\u003e (41 and 1 patients who received study transplantation and post-study transplantation, respectively)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eToxicity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003egrade\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e% of patients (n)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95.2 (40)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e92.9 (39)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT-bilirubin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.1 (3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u0026thinsp;+\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19.0 (8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u0026thinsp;+\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.4 (9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eγ-GTP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38.1 (16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eErythema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14.3 (6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAppetite loss\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33.3 (14)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMucositis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35.7 (15)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.7 (7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVomiting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.1 (3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhoea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.4 (9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHaemorrhagic cystitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.4 (1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenic fever with G3\u0026ndash;4 neutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57.1 (24)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumonitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.8 (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment-related death\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe patient flow diagram is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Among all 110 enrolled patients, 5 were found to be ineligible after enrolment (favourable chronic type ATL, n\u0026thinsp;=\u0026thinsp;1; inappropriate organ function, n\u0026thinsp;=\u0026thinsp;1; complication of another cancer, n\u0026thinsp;=\u0026thinsp;1; HL, n\u0026thinsp;=\u0026thinsp;1; no documented informed consent left that was relieved with regaining written IC: n\u0026thinsp;=\u0026thinsp;1.\u003c/p\u003e \u003cp\u003eAll 110 enrolled patients received first-line chemotherapy. Among those, 3 patients received VCAP-AMP-VECP combined with mogamulizumab as the protocol treatment. Among these 3 patients, 2 in off-protocol transplantation group died due to TRD, and 1 in no transplantation group died due to PD. Of the 110 patients, 49 (45%) acquired a donor according to study regulations (acquisition of protocol donor group); of these, 41 received per-protocol allo-HSCT (study transplantation group). The details of the study transplantation group are as follows: 19 underwent MAST and 22 underwent RIST according to the conditioning regimen, while 12 had related donors and 29 had unrelated donors. Meanwhile, among 69 patients (no study transplantation group), which included 61 who did not acquire a protocol donor and 8 who did not achieve study transplantation despite acquiring a protocol donor (progressive disease [PD] during preparation for transplantation, n\u0026thinsp;=\u0026thinsp;4; non-regulated transplantation procedure, n\u0026thinsp;=\u0026thinsp;2; suspension of harvest due to health problem of donor, n\u0026thinsp;=\u0026thinsp;1; transfer to a non-participant institute, n\u0026thinsp;=\u0026thinsp;1), 51 patients received off-protocol transplantation. The details of those 51 patients are as follows: 35 underwent transplantation during first remission/stable disease and 16 underwent transplantation after progression/relapse according to disease status, 11 received MAST and 40 received RIST according to the conditioning regimen, and 11 had related, 15 had unrelated, and 25 had cord blood (CB) donors. Finally, a total of 92 patients received allo-HSCT of various types (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEfficacy\u003c/h3\u003e\n\u003cp\u003eThe median follow-up period of all 110 enrolled patients was 22.0 months (IQR, 10.2\u0026ndash;54.6). The trial met the primary endpoint of 3-year OS of 44.0% (90% CI, 36.0\u0026ndash;51.6), exceeding the predefined threshold of 25% (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWith respect to the secondary endpoint, the median survival times (MST) for the acquisition of protocol donor group (n\u0026thinsp;=\u0026thinsp;49) and no acquisition of protocol donor group (n\u0026thinsp;=\u0026thinsp;61) were 3.4 years (95% CI, 1.6\u0026ndash;6.9) and 1.2 years (95% CI, 0.9\u0026ndash;4.3), respectively (Supplement Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). The MST for the study transplantation group (n\u0026thinsp;=\u0026thinsp;41) and no study transplantation group (n\u0026thinsp;=\u0026thinsp;69) were 3.0 years (95% CI, 1.5\u0026ndash;5.8) and 1.3 years (95% CI, 0.9\u0026ndash;4.6), respectively. The MST for the all transplantation group (n\u0026thinsp;=\u0026thinsp;92) and no transplantation group (n\u0026thinsp;=\u0026thinsp;18) was 2.5 years (95% CI, 1.4\u0026ndash;4.8) and 0.9 years (95% CI, 0.4\u0026ndash;1.2), respectively. Among all 92 transplantation patients, the MST for related, unrelated, and cord blood (CB) transplantation showed no significant difference, with 2.4 years (95% CI, 1.1 to not estimable), 3.4 years (95% CI, 1.5\u0026ndash;6.9), and 1.4 years (95% CI, 0.9\u0026ndash;10.5), respectively (Supplement Figure S2).\u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003eA shows the timing of transplantation and survival. The median time from diagnosis to transplantation was similar in the study transplantation group and the group that received off-protocol transplantation. Allo-HSCT potentially has an immortal time bias because only patients who survive through chemotherapy can achieve allo-HSCT. To reduce this bias, we performed a multivariable analysis, using a time-dependent covariate for the presence or absence of transplantation. Univariable analysis revealed that the hazard ratio (HR) for OS of the study transplantation group (n\u0026thinsp;=\u0026thinsp;41) relative to the no study transplantation group (n\u0026thinsp;=\u0026thinsp;69) was 0.944 (95% CI, 0.575\u0026ndash;1.549). Multivariable analysis showed that the HR for OS of the study transplantation group relative to the no study transplantation group was 0.915 (95% CI, 0.554\u0026ndash;1.512) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). Univariable analysis revealed that the HR for OS of the all transplantation group (n\u0026thinsp;=\u0026thinsp;92) relative to the no transplantation group (n\u0026thinsp;=\u0026thinsp;18) was 0.882 (95% CI, 0.437\u0026ndash;1.780). Multivariable analysis showed that the HR for OS of the all transplantation group relative to the no transplantation group was 0.896 (95% CI, 0.446\u0026ndash;1.800) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003eC). In further analysis, univariable analysis revealed that the HR for OS of the upfront setting transplantation group (excluding transplantation after progression/relapse, n\u0026thinsp;=\u0026thinsp;76; study transplantation, n\u0026thinsp;=\u0026thinsp;41; off-protocol transplantation, n\u0026thinsp;=\u0026thinsp;35) relative to the no transplantation group (n\u0026thinsp;=\u0026thinsp;18) was 0.635 (95% CI, 0.317\u0026ndash;1.275). Multivariable analysis showed that the HR for OS of the upfront setting transplantation group relative to the no transplantation group was 0.654 (95% CI, 0.326\u0026ndash;1.311) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003eD).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eIn this trial, there was no TRD during chemotherapy. Among the 41 patients in the study transplantation group, TRD in related transplantation and unrelated transplantation were 16.7% (related transplantation, n\u0026thinsp;=\u0026thinsp;2/12) and 20.7% (unrelated transplantation, n\u0026thinsp;=\u0026thinsp;6/29), respectively. Among 42 patients (study transplantation, n\u0026thinsp;=\u0026thinsp;41; CBT after completion of conditioning regimen as study treatment, n\u0026thinsp;=\u0026thinsp;1) who received allo-HSCT and had available data for toxicities, grade 4 neutropenia was observed in 95.2% (n\u0026thinsp;=\u0026thinsp;40/42), and grade 4 thrombocytopenia in 92.9% (n\u0026thinsp;=\u0026thinsp;39/42). Grade 3\u0026ndash;4 elevation of total bilirubin, AST, ALT, and γ-GTP were observed in 7.1% (n\u0026thinsp;=\u0026thinsp;3/42), 19.0% (n\u0026thinsp;=\u0026thinsp;8/42), 21.4% (n\u0026thinsp;=\u0026thinsp;9/42), and 38.1% (n\u0026thinsp;=\u0026thinsp;16/42), respectively. Adverse events associated with GVHD included grade 3\u0026ndash;4 skin rash in 14.3% (n\u0026thinsp;=\u0026thinsp;6/42), diarrhoea in 21.4% (n\u0026thinsp;=\u0026thinsp;9/42), and pneumonitis in 4.8% (n\u0026thinsp;=\u0026thinsp;2/42). Causes of death for all 70 patients included ATL (n\u0026thinsp;=\u0026thinsp;34), TRD due to study transplantation (n\u0026thinsp;=\u0026thinsp;9), TRD due to post-study treatment (n\u0026thinsp;=\u0026thinsp;21), and other diseases (n\u0026thinsp;=\u0026thinsp;6; lung cancer, myelodysplastic syndrome, cerebral haemorrhage, acute myeloid leukemia, aspiration pneumonia, coronavirus disease 2019 pneumonia).\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis is the first well-designed and confirmatory single-arm, phase 3 trial on the treatment strategy of upfront allo-HSCT after intensive chemotherapy for patients with untreated aggressive ATL. Conducting a randomised controlled trial for the presence or absence of allo-HSCT is extremely difficult as only some selected patients with suitable donors can receive it. This trial met the primary endpoint, with the lower limit of the 90% CI for 3-year OS (36.0%) exceeding the threshold of 25% set by JCOG9801 [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Allo-HSCT potentially has an immortal time bias, as only patients who survive prior chemotherapy can receive it. To evaluate this issue, we performed a multivariable analysis with a time-dependent covariate in addition to the primary endpoint. The HR in OS of the study transplantation group relative to the no study transplantation group was 0.915 (95% CI, 0.554\u0026ndash;1.512), suggesting there is no survival benefit of study transplantation. On the other hand, the HR in OS of the upfront transplantation group (n\u0026thinsp;=\u0026thinsp;76 patients [study transplantation, n\u0026thinsp;=\u0026thinsp;41; off-protocol transplantation during remission/stable disease status, n\u0026thinsp;=\u0026thinsp;35) relative to the no transplantation group (n\u0026thinsp;=\u0026thinsp;18) was 0.654 (95% CI, 0.326\u0026ndash;1.311), suggesting that upfront allo-HSCT has better survival outcomes. However, it is important to note that the patient population who received transplantation in their first remission/stable disease may be in a relatively better condition, and that patients who underwent a transplantation after progression/relapse\u0026mdash;and who potentially had a poor prognosis\u0026mdash;were excluded. Consequently, these data indicate that the survival benefit of study transplantation in this trial for patients with aggressive ATL remains unclear.\u003c/p\u003e \u003cp\u003eThis trial initially started using only MAST for patients of \u0026le;\u0026thinsp;55 years of age as study transplantation from September 2010. However, some promising results regarding RIST for older patients with aggressive ATL have been reported [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], and the protocol was amended to incorporate RIST and expand the age group to 56\u0026ndash;65 years from September 2014. On the other hand, the protocol treatment permitted HLA identical or 1 locus mismatched sibling, or HLA identical unrelated donors excluding CB as eligible donors during the whole study period because CBT was identified as a poor risk factor in the Japanese nationwide retrospective study of allo-HSCT for aggressive ATL [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. After the 2010s, the feasibility of CBT for patients with aggressive ATL was demonstrated in some analyses [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Furthermore, allo-HSCT from HLA-haploidentical related donors has also been attempted for aggressive ATL recently [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The prospective observational study between 2015 and 2018 in Japan demonstrated that 2-year probabilities of OS of 90 patients who received allo-HSCT (CB, n\u0026thinsp;=\u0026thinsp;30; HLA-haploidentical related donor, n\u0026thinsp;=\u0026thinsp;20; other related donor, n\u0026thinsp;=\u0026thinsp;14; other unrelated donor, n\u0026thinsp;=\u0026thinsp;26) was 44%, and OS did not differ statistically according to donor type [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In this trial among 51 patients who received off-protocol transplantation, 25 patients (in remission, n\u0026thinsp;=\u0026thinsp;17; in progression/relapse, n\u0026thinsp;=\u0026thinsp;8) and 2 patients (in remission, n\u0026thinsp;=\u0026thinsp;2) received CBT and haploidentical transplantation, respectively. There was no significant difference in MST among related, unrelated, and CB transplantation in 92 patients of the all transplantation group, suggesting the availability of CB as a donor source for allo-HSCT for untreated aggressive ATL.\u003c/p\u003e \u003cp\u003eIn this trial, the proportions of deaths due to disease progression and TRD were relatively high. The TRD rate of allo-HSCT for patients with aggressive ATL has been reported to be higher relative to other hematologic malignancies [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The Japanese nationwide retrospective study demonstrated that cumulative incidence rates of TRD at 3 years after transplantation in HLA-matched related, HLA-mismatched related, unrelated and CB transplantation, were 37%, 43%, 42%, and 52%, respectively [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In this trial, the TRD rate among 41 patients who received study transplantation was 16.7% (2/12) in related transplantation and 20.7% (6/29) in unrelated transplantation. These were below the prespecified permissible rates of TRD (30% and 35% in related and unrelated transplantation, respectively). The TRD rate in this trial may be underestimated because data from 1 patient (excluded due to lack of informed consent document) who died from transplantation-related complications was eliminated. Additionally, there were no detailed data for patients who received off-protocol transplantation. However, HLA-matched and 1 locus mismatched related, as well as HLA-matched unrelated transplantation, were considered to be tolerable treatment procedures for patients with aggressive ATL in this trial.\u003c/p\u003e \u003cp\u003eDisease progression is more common in ATL compared with other aggressive lymphomas, both with chemotherapy alone and with chemotherapy followed by allo-HSCT. Further efforts are needed to improve the prognosis of aggressive ATL. One possibility is adding molecular targeting agents in combination with chemotherapy or as maintenance after allo-HSCT. Several promising new agents for aggressive ATL include mogamulizumab, lenalidomide, tucidinostat, and valemetostat [\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Mogamulizumab should be carefully considered immediately before allo-HSCT and after allo-HSCT due to the potential for worsening GVHD [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. However, combining mogamulizumab with chemotherapy has shown promise in prospective and retrospective studies of transplantation ineligible ATL patients [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Using this agent at the appropriate timing may improve the results of allo-HSCT-containing therapy for aggressive ATL. Secondly, improving allo-HSCT itself, as mentioned above, is essential. Lastly, early intervention is important for better managing relapse before and after allo-HSCT.\u003c/p\u003e \u003cp\u003eThe limitations of this trial included the enrolment of 51 patients who received off-protocol transplantation and 2 patients with ineligible disease types (favourable chronic ATL and HL). These deviations complicated the evaluation of the study results. Although the trial met its primary endpoint, the survival benefit of study transplantation for patients with aggressive ATL remains unclear. This is due to the immortal time bias suggested by the HR of 0.915 (95% CI, 0.554\u0026ndash;1.512) for OS in the study transplantation group (n\u0026thinsp;=\u0026thinsp;41) compared to the no study transplantation group (n\u0026thinsp;=\u0026thinsp;69) in a multivariable analysis with a time-dependent covariate for the presence or absence of transplantation. Furthermore, to evaluate the significance of upfront allo-HSCT for patients with aggressive ATL as a basic concept for the treatment strategy of this trial, we calculated the HR for OS of the upfront setting transplantation group (n\u0026thinsp;=\u0026thinsp;76 [study transplantation, n\u0026thinsp;=\u0026thinsp;41; off-protocol transplantation, n\u0026thinsp;=\u0026thinsp;35]) relative to the no transplantation group (n\u0026thinsp;=\u0026thinsp;18). The HR was 0.654 (95% CI 0.326\u0026ndash;1.311) in a multivariable analysis. This result suggests that upfront allo-HSCT could be recommended for chemotherapy-sensitive patients with aggressive ATL.\u003c/p\u003e \u003cp\u003eIn conclusion, the strategy of upfront allo-HSCT after intensive chemotherapy can be recommended for untreated aggressive ATL, despite the relatively high proportion of disease progression and TRD as causes of death. However, the survival benefit of study transplantation in this trial remains unclear.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported in part by the National Cancer Center Research and Development Fund (29-A-3, 2020-J-3, 2023-J-03) from the Ministry of Health, Labour and Welfare of Japan. We thank all the patients and their families, all the study site coordinators and investigators, and the data managers at the JCOG Data Center.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConception and design:\u003c/strong\u003e T Fukushima, K Tsukasaki, T Shibata, H Fukuda\u003c/p\u003e\n\u003cp\u003eAdministrative support: H Nagai\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProvision of study materials and patients:\u003c/strong\u003e T Fukushima, K Tsukasaki, D Maruyama, S Makita, S Kusumoto, S Iida, M Tokunaga, Y Miyazaki, M Yoshimitsu, I Choi, K Morichika, K Miyazaki, J Makiyama, K Nosaka, H Katsuya, T Kawakita, Y Minami, S Ota, T Uchida, N Kubota, Y Harada, K Takase\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCollection and assembly of data:\u003c/strong\u003e R Machida, T Shibata, H Fukuda\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData analysis and interpretation:\u003c/strong\u003e T Fukushima, K Tsukasaki, R Machida, T Shibata, H Fukuda, H Nagai\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eManuscript writing:\u003c/strong\u003e All authors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinal approval of manuscript:\u003c/strong\u003e All authors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAccountable for all aspects of the work:\u003c/strong\u003e All authors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTakuya Fukushim\u003c/strong\u003ea\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResearch Funding:\u003c/strong\u003e Daiichi-Sankyo\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHonoraria:\u003c/strong\u003e Meiji Seika Pharma, AstraZeneca, Daiichi-Sankyo, Chugai Pharmaceutical, Bristol Myers Squibb, Kyowa Kirin, Novartis, Amgen.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eKunihiro Tsukasaki\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResearch Funding:\u003c/strong\u003e Kyowa Kirin, Meiji Seika Pharma, Bristol Myers Squibb, Byer, Daiichi-Sankyo\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHonoraria:\u003c/strong\u003e Eisai, Takeda, Meiji Seika Pharma, Sekisui Medical, Daiichi-Sankyo, Nippon-Shinyaku\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsulting or Advisory Role:\u003c/strong\u003e Meiji Seika Pharma, Daiichi-Sankyo.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRyunosuke Machida\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eShinichi Makita\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHonoraria:\u003c/strong\u003e AstraZeneca, BMS, Chugai, Genmab, Gilead, Kyowa Kirin, Novartis, Takeda.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eShigeru Kusumoto\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResearch Funding:\u003c/strong\u003e Daiichi-Sankyo, Bristol Myers Squibb, Chugai, Ono, Genmab, Meiji Seika Pharma, Janssen, Takeda, AbbVie, Shionogi\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHonoraria:\u003c/strong\u003e Chugai, Eisai, Janssen, Meiji Seika Pharma, AbbVie, Nippon Shinyaku, Astellas, Novartis, Zenyaku, Fujimoto, Daiichi-Sankyo, SymBio, Ono, Lilly, Genmab, Sanofi, Takeda, Sumitomo, Mundi Pharma, AstraZeneca.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsulting or Advisory Role:\u003c/strong\u003e Daiichi-Sankyo, Lilly, Chugai, Kyowa Kirin, Genmab, Janssen\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eShinsuke Iida\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResearch Funding:\u003c/strong\u003e Pfizer, Bristol Myers Squibb, Janssen, Sanofi, Takeda, Chugai, AstraZeneca, Ono, Shionogi, Glaxo SmithKein, Daiichi-Sankyo, AbbVie, Amgen, Otsuka, Alexion, Novartis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHonoraria:\u003c/strong\u003e Bristol Myers Squibb, Pfizer, Janssen, Sanofi, Takeda, Ono, AstraZeneca.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMasahito Tokunaga\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHonoraria:\u003c/strong\u003e Meiji Seika Pharma and Minophagen.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYasushi Miyazaki\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHonoraria:\u003c/strong\u003e Kyowa Kirin, Chugai, Takeda\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eleadership or fiduciary role in other board, society, committee or advocacy group:\u003c/strong\u003e Japan Adult Leukemia Study Group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMakoto Yoshimitsu\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHonoraria:\u003c/strong\u003e Takeda, Sanofi, Novartis, Chugai, PharmaEssentia, Astellas, Genmab, Ono, Daiichi-Sankyo, Nippon Shinyaku, Bristol Myers Squibb, Eisai, Kissei, Nippon Kayaku, Meiji Seika Pharma\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIlseung Choi\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eKazuho Morichika\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eKana Miyazaki\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResearch Funding\u003c/strong\u003e:\u0026nbsp;Takeda, Otsuka, Chugai, Kyowa Kirin, Sumitomo, Zenyaku Kogyo; \u003cstrong\u003eHonoraria:\u003c/strong\u003e Chugai, Janssen, AstraZeneca, Novartis, Incyte, Asahi Kasei, Abbvie, SymBio, Ono, Genmab, Meiji Seika Pharma, Bristol Myers Squibb, Kyowa Kirin, Daiichi-Sankyo, Gilead, Nippon Shinyaku\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJunya Makiyama\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHonoraria:\u003c/strong\u003e AbbVie, Chugai, Janssen, Meiji Seika Pharma, Otsuka, Symbio, Bristol Myers Squibb, Daiichi-Sankyo, Kyowa Kirin, Ono, Sanofi, Takeda\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eKisato Nosaka\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResearch Funding:\u003c/strong\u003e Kyowa Kirin, Chugai\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHonoraria:\u003c/strong\u003e Meiji Seika Pharma, Chugai, Bristol Myers Squibb, Kyowa Kirin, AbbVie, Daiichi-Sankyo, Eisai, Ohara, Janssen, Minophagen\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHiroo Katsuya\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eToshiro Kawakita\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYosuke Minami\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHonoraria:\u003c/strong\u003e Astellas, Novartis, Daiichi-Sankyo, Pfizer, and Otsuka\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsulting or Advisory Role:\u003c/strong\u003e Takeda, Novartis, CMIC\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eShuichi Ota\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHonoraria:\u003c/strong\u003e Novartis, Takeda, AstraZeneca, AbbVie, ParmaEssentia, Bristol Myers Squibb, Janssen, Amgen, Sanofi\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eToshiki Uchida\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHonoraria:\u003c/strong\u003e Novartis, Janssen, AbbVie, Nippon Shinyaku, Meiji Seika Pharma, Eisai, Chugai, Asahi Kasei, Kissei, Sanofi, Bristol Myers Squibb, Kyowa Kirin, Nippon Kayaku, Takeda\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNobuko Kubota\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYasuhiko Harada\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eKen Takase\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTaro Shibata\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHaruhiko Fukuda\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResearch Funding:\u003c/strong\u003e AstraZeneca, Ono, Chugai, Takeda\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHonoraria:\u003c/strong\u003e Chugai, Kyowa Kirin, CMIC.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHirokazu Nagai\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResearch Funding:\u003c/strong\u003e AbbVie, AstraZeneca, Beigene, Genmab, Incyte Biosciences Japan, Janssen, Lilly, Takeda, Kyowa Kirin, MSD, Mitsubishi Tanabe, Chugai, Daiichi-Sankyo, Celgen, Zenyaku Kogyo, Solasia, Ono Regeneron, Haihe\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHonoraria:\u003c/strong\u003e AbbVie, AstraZeneca, Genmab, Janssen, Eli Lilly, Takeda, Kyowa Kirin, MSD, Eisai, Novartis, Ono, Dainippon Sumitomo, Chugai, Meiji Seika Pharma, Mundi Pharma, GSK, BMS, Nippon Kayaku, Nippon Shinyaku, Beigene\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDai Marumaya\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResearch Funding:\u003c/strong\u003e Ono, Janssen, Eisai, Chugai, Kyowa Kirin, MSD, Zenyaku, Sanofi, Symbio, Takeda, AbbVie, AstraZeneca, BMS，Genmab Novartis, Otsuka, Taiho, Pfizer, Astellas\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHonoraria:\u003c/strong\u003e Ono Nippon Shinyaku, Janssen, Mundipharma, Eisai, Chugai, Kyowa Kirin, MSD, Zenyaku Sanofi, Symbio, Takeda, AbbVie, AstraZeneca, BMS, Genmab, Novartis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsulting or Advisory Role:\u003c/strong\u003e Janssen, AstraZeneca, Chugai, AbbVie, Genmab, Sanofi, BMS, Pfizer.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIndividual participant data that underlie the results reported in this article, after deidentification will be shared if investigators whose proposed use of the data has been approved by the investigators from Lymphoma Study Group of JCOG identified for this purpose. Proposals should be directed to [email protected]. The data will be available for achieving aims in the approved proposal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCLINICAL TRIAL INFORMATION\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ejRCTs031180243\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eUchiyama T, Sagawa K, Takatsuki K, Uchino H. Adult T-cell leukemia: clinical and hematologic features of 16 cases. \u003cem\u003eBlood\u003c/em\u003e 1977; 50: 481\u0026ndash;492.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePoiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC. 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A phase 2 trial of CHOP with anti-CCR4 antibody mogamulizumab for elderly patients with adult T-cell leukemia/lymphoma. \u003cem\u003eBlood\u003c/em\u003e 2025; 146: 1440\u0026ndash;1449.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bone-marrow-transplantation","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bmt","sideBox":"Learn more about [Bone Marrow Transplantation](http://www.nature.com/bmt/)","snPcode":"41409","submissionUrl":"https://mts-bmt.nature.com/cgi-bin/main.plex","title":"Bone Marrow Transplantation","twitterHandle":"@bmtjournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8095067/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8095067/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis single-arm, phase 3 trial by the Japan Clinical Oncology Group evaluated the strategy of upfront allogeneic hematopoietic stem cell transplantation (allo-HSCT) after intensive chemotherapy for untreated aggressive adult T-cell leukemia-lymphoma (ATL).\u003c/p\u003e \u003cp\u003ePatients\u0026thinsp;\u0026le;\u0026thinsp;65 years old with aggressive ATL were eligible. The protocol-treatment was VCAP-AMP-VECP as induction-chemotherapy followed by allo-HSCT in first remission.\u003c/p\u003e \u003cp\u003eBetween 2010 and 2020, 110 patients were enrolled. Among all 92 transplantations, 41 under per-protocol (study transplantation) and 51 under off-protocol received allo-HSCT. The primary endpoint was met with 3-year OS of 44.0% (90% CI, 36.0\u0026ndash;51.6\u0026thinsp;\u0026gt;\u0026thinsp;25.0). The median survival time of the study transplantation and all transplantation was 3.0 (95% CI, 1.5\u0026ndash;5.8) and 2.5 years (95% CI, 1.4\u0026ndash;4.8), respectively. Multivariable analysis with a time-dependent covariate for transplantation revealed that the hazard ratio for OS of study transplantation was 0.915 (95% CI, 0.554\u0026ndash;1.512). In study transplantation, the rate of treatment-related death (TRD) in related and unrelated transplantation was 16.7% and 20.7%, respectively. Thirty-four deaths due to disease progression (PD) were observed.\u003c/p\u003e \u003cp\u003eUpfront allo-HSCT can be recommended for aggressive ATL despite a relatively high rate of PD and TRD. However, the survival benefit of study transplantation remains unclear considering the immortal bias.\u003c/p\u003e","manuscriptTitle":"Upfront allo-HSCT after intensive chemotherapy for untreated aggressive ATL: A single arm, phase 3 trial, JCOG0907","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-22 09:20:16","doi":"10.21203/rs.3.rs-8095067/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bone-marrow-transplantation","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bmt","sideBox":"Learn more about [Bone Marrow Transplantation](http://www.nature.com/bmt/)","snPcode":"41409","submissionUrl":"https://mts-bmt.nature.com/cgi-bin/main.plex","title":"Bone Marrow Transplantation","twitterHandle":"@bmtjournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"af1f4425-a828-4a57-b366-cad2aa902d5b","owner":[],"postedDate":"December 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":58007262,"name":"Health sciences/Medical research/Clinical trial design/Clinical trials/Phase III trials"},{"id":58007263,"name":"Health sciences/Diseases"}],"tags":[],"updatedAt":"2025-12-22T09:20:16+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-22 09:20:16","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8095067","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8095067","identity":"rs-8095067","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}