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

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 .