Upfront allo-HSCT after intensive chemotherapy for untreated aggressive ATL: JCOG0907, a single-arm, phase 3 trial.
Authors: Takuya Fukushima, Kunihiro Tsukasaki, Ryunosuke Machida, Dai Maruyama, Shinichi Makita, Shigeru Kusumoto, Shinsuke Iida, Masahito Tokunaga, Yasushi Miyazaki, Makoto Yoshimitsu, Ilseung Choi, Sawako Nakachi, Kana Miyazaki, Junya Makiyama, Kisato Nosaka, Hiroo Katsuya, Toshiro Kawakita, Taro Shibata, Haruhiko Fukuda, Hirokazu Nagai
Journal: Journal of Clinical Oncology (2024)

7001 Background: Aggressive adult T-cell leukemia-lymphoma (ATL) (i.e., acute, lymphoma and unfavorable chronic types) has poor prognosis with around a 1-year median survival time (MST) with chemotherapy. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides a durable response with 3-year overall survival (3-y OS) of around 40%. However, the results were mostly from retrospective studies. This single-arm, phase 3 trial by the Japan Clinical Oncology Group (JCOG) evaluated upfront allo-HSCT for aggressive ATL (jRCTs031180243). Methods: Patients (pts) with newly diagnosed aggressive ATL who wished to receive allo-HSCT were eligible. At trial initiation, JCOG0907 was restricted to myeloablative allo-HSCT (MAST) for pts aged ≤ 55 years. After protocol amendment in September 2014, reduced intensity allo-HSCT (RIST) for pts aged 56-65 years was allowed. The protocol treatment was VCAP-AMP-VECP as induction chemotherapy based on the phase 3 JCOG9801 trial (3-y OS 24%) followed by transplantation in pts upon first remission from an HLA-matched or 1-locus mismatched related donor, or HLA-matched unrelated (UR) donor. MAST regimens consisted of busulfan (BU)/cyclophosphamide (CPA) for related donors and total body irradiation (TBI)/CPA for UR donors. RIST regimens consisted of BU/fludarabine (FLU) for related donors and FLU/BU/TBI for UR donors. The primary endpoint was 3-y OS in all registered pts. This study evaluated whether the lower limit of the two-sided 90% CI of 3-y OS exceeded a threshold of 25%. Results: Between September 2010 and June 2020, 110 pts (72 acute, 27 lymphoma, 10 unfavorable chronic and 1 other) were enrolled. Of 92 pts who received allo-HSCT (all transplants), 41 pts (19 MAST and 22 RIST, 12 related and 29 UR) received per-protocol allo-HSCT (study transplant) and 51 pts (11 related, 15 UR and 25 cord blood) received allo-HSCT not specified in the protocol, 35 of whom received allo-HSCT during first remission and 16 pts after progression. The primary endpoint was met with 3-y OS of 44.0% (90% CI, 36.0-51.6). MST was 3.0 years (95% CI, 1.5-5.8) for study transplants and 2.5 years (95% CI, 1.4-4.8) for all transplants. Multivariable analysis with a time-dependent covariate for the presence or absence of transplant revealed the hazard ratio of OS for study transplants compared with non-study transplants was 0.92 (95% CI, 0.55-1.51). In 41 study transplants, treatment-related deaths (TRD) were 16.7% in related transplants and 20.7% in UR transplants. Among 70 pts who died, causes of death were disease progression in 34, TRD due to protocol treatment in 9, TRD due to post-protocol treatment in 21, and other disease in 6. Conclusions: Upfront allo-HSCT can be recommended for chemotherapy-sensitive pts with aggressive ATL, but its survival benefit is not clear considering immortal time bias suggested by multivariable analysis with a time-dependent covariate. Clinical trial information: jRCTs031180243 .