Key Points• Risk stratification treatment of t(8;21) acute myeloid leukemia may decrease relapse and improve longterm survival.• Allo-HSCT benefited high-risk patients, but impaired the survival of low-risk patients.We aimed to improve the outcome of t(8;21) acute myeloid leukemia (AML) in the first complete remission (CR1) by applying risk-directed therapy based on minimal residual disease (MRD) determined by RUNX1/RUNX1T1 transcript levels. Risk-directed therapy included recommending allogeneic hematopoietic stem cell transplantation (allo-HSCT) for high-risk patients and chemotherapy/autologous-HSCT (auto-HSCT) for low-risk patients. Among 116 eligible patients, MRD status after the second consolidation rather than induction or first consolidation could discriminate high-risk relapse patients (P 5 .001).Allo-HSCT could reduce relapse and improve survival compared with chemotherapy for high-risk patients (cumulative incidence of relapse [CIR]: 22.1% vs 78.9%, P < .0001; disease-free survival [DFS]: 61.7% vs 19.6%, P 5 .001), whereas chemotherapy/auto-HSCT achieved a low relapse rate (5.3%) and high DFS (94.7%) for low-risk patients. Multivariate analysis revealed that MRD status and treatment choice were independent prognostic factors for relapse, DFS, and OS. We concluded that MRD status after the second consolidation may be the best timing for treatment choice. MRD-directed risk stratification treatment may improve the outcome of t(8;21) AML in CR1. This trial was registered at http://www.chictr.org as #ChiCTR- OCH-12002406. (Blood. 2013;121(20):4056-4062)

We studied the impact of risk stratificationdirected interventions for minimal residual disease (MRD) on relapse and disease-free survival (DFS) prospectively in 814 subjects with standard-risk acute leukemia receiving allotransplantation in first or second complete remission. A total of 709 subjects were MRD ؊ after transplantation (Group A); 105 subjects were MRD ؉ , 49 received low-dose IL-2 (Group B), and 56 received modified donor lymphocyte infusion (DLI) with or without low-dose IL-2 (Group C).Posttransplantation immune suppression for GVHD was also modified based on MRD state. The cumulative risk of relapse was significantly less and DFS was significantly better in subjects in Group C than in subjects in Group B (P ‫؍‬ .001 and P ‫؍‬ .002, respectively), but was not different from subjects in Group A (P ‫؍‬ .269 and P ‫؍‬ .688, respectively

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in clinical development for the treatment of human epidermal growth factor receptor 2 (HER2)-positive cancers. Herein, we describe a series of studies to assess T-DM1 absorption, distribution, metabolism, and excretion (ADME) in rats as well as to assess human exposure to T-DM1 catabolites. Following administration of unlabeled and radiolabeled T-DM1 in female Sprague Dawley rats as a single dose, plasma, urine, bile and feces were assessed for mass balance, profiling and identification of catabolites. In rats, the major circulating species in plasma was T-DM1, while DM1 concentrations were low (1.08 to 15.6 ng/mL). The major catabolites found circulating in rat plasma were DM1, [N-maleimidomethyl] cyclohexane-1- carboxylate-DM1 (MCC-DM1), and Lysine-MCC-DM1. These catabolites identified in rats were also detected in plasma samples from patients with HER2-positive metastatic breast cancer who received single-agent T-DM1 (3.6 mg/kg every 3 weeks) in a phase 2 clinical study. There was no evidence of tissue accumulation in rats or catabolite accumulation in human plasma following multiple dosing. In rats, T-DM1 was distributed nonspecifically to the organs without accumulation. The major pathway of DM1-containing catabolite elimination in rats was the fecal/biliary route, with up to 80% of radioactivity recovered in the feces and 50% in the bile. The rat T-DM1 ADME profile is likely similar to the human profile, although there may be differences since trastuzumab does not bind the rat HER2- like receptor. Further research is necessary to more fully understand the T-DM1 ADME profile in humans.

Key Points• RUNX1/RUNX1T1-based MRD status at 1, 2, and 3 months after HSCT could discriminate patients at high risk of post-HSCT relapse.• Rather than c-KIT mutations, MRD monitoring allows further rapid identification of patients at high risk of relapse after allo-HSCT.We asked whether minimal residual disease (MRD) determined by RUNX1/RUNX1T1 transcript levels could identify allogeneic hematopoietic stem cell transplantation (allo-HSCT) t(8;21) (q22;q22) acute myeloid leukemia patients who are at high risk for relapse, together with the impact of c-KIT mutations. Ninety-two consecutive adult t(8;21) patients who received allo-HSCT in complete remission were enrolled. MRD status at 1, 2, and 3 months after HSCT identified relapse patients (P 5 .05, P < .001, P 5 .0001, respectively). The 2-year cumulative incidence of relapse (CIR) and leukemia-free survival (LFS) was 32% vs 9% (P 5 .01) and 55% vs 70% (P 5 .12) for patients with and without c-KIT mutations, respectively. In multivariate analysis, MRD at the first 3 months after HSCT, rather than c-KIT mutations, was an independent factor for CIR (P 5 .001) and LFS (P 5 .001).In addition, 17 patients received donor lymphocyte infusion (DLI) as interventional therapy for MRD, and the 2-year CIR and LFS for patients with or without DLI was 24% vs 87% (P 5 .001) and 64% vs 0% (P < .001), respectively. In conclusion, MRD monitoring early after transplant allows further rapid identification of t(8;21) patients at high risk of relapse and was more predictive of relapse risk than

Either WT1 or leukemia-associated aberrant immune phenotypes (LAIPs) was one of the minimal residual disease (MRD) parameters used to predict leukemia relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We first evaluated the clinical value of various positive MRD standards for accurately indicating relapse based on WT1 and FCM data in adult patients with acute leukemia (AL). In total, 824 AL patients treated with allo-HSCT were enrolled in this study. We compared the sensitivity and specificity of diverse, multiple-criteria MRD prognostic standards based on WT1 and FCM assays. Higher sensitivity was achieved without a loss of specificity when MRDco+, which was defined as two consecutive WT10.6+ or FCM+ or both WT10.6+ and FCM+ in the same sample within a year posttransplantation, was used as the positive MRD standard. Similar results were observed, even in 484 patients who had both abnormal WT1 and LAIPs values before transplant. A multivariate analysis showed that MRDco+ was an independent risk factor for leukemia relapse after transplant in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). The combined use of FCM and WT1 monitoring could distinguish between patients with low and high risks of relapse. Various positive MRD standards were useful for guiding intervention.