We conducted a retrospective analysis of 968 adults with acute myeloid leukemia (AML) on 5 recent Southwest Oncology Group trials to understand how the nature of AML changes with age. Older study patients with AML presented with poorer performance status, lower white blood cell counts, and a lower percentage of marrow blasts. Multidrug resistance was found in 33% of AMLs in patients younger than age 56 compared with 57% in patients older than 75. The percentage of patients with favorable cytogenetics dropped from 17% in those younger than age 56 to 4% in those older than 75. In contrast, the proportion of patients with unfavorable cytogenetics increased from 35% in those younger than age 56 to 51% in patients older than 75. Particularly striking were the increases in abnormalities of chromosomes 5, 7, and 17 among the elderly. The increased incidence of unfavorable cytogenetics contributed to their poorer outcome, and, within each cytogenetic risk group, treatment outcome dete-

Summary Background Gemtuzumab Ozogamicin (GO) was the first example of antibody directed chemotherapy in cancer and developed for Acute Myeloid Leukaemia. Its role has been unclear. Five randomised trials where it was combined with standard induction chemotherapy in adults have produced different results. In an effort to clarify the level of benefit, if any, and in which patients outcomes might be improved, an individual patient data meta-analysis of these 5 trials has been undertaken. Methods All randomised trials of GO in adults (age >15), given in conjunction with the first course of intensive induction chemotherapy for AML (excluding APL) were identified. In a collaboration between the groups involved, source data concerning demographics, treatment was requested in May 2013 and collected in 3325 randomised patients (median age 58). All trials were centrally randomised and open-label, with survival as primary endpoint. Analyses are presented by standard techniques, and within standardised risk groups Results Remission rates were not increased, but by significantly reducing the risk of relapse overall survival at 5 years was improved irrespective of patient age (30.7% vs 34.6%; HR 0.90 (95% CI 0.82-0.98), p=0.01). The survival benefit was particularly clear in those with favourable cytogenetics (55.2% vs 76.3%; HR0.47 (0.31-0.73), p=0.0005), but also observed in intermediate risk patients (34.1% vs 39.4%; HR 0.84 (0.75-0.95), p=0.007) Patients with adverse karyotype did not benefit overall or within any trial. Dose levels of 3mg/m2 were associated with less toxicity and equal efficacy. Interpretation GO can be safely added to conventional induction therapy. For patients who do not have adverse cytogenetics there is a significant survival benefit. These data suggest that the use of GO should be re-evaluated and the license status of GO may need to be reviewed. Role of funding source There was no funder for this meta-analysis.

Key Points• The addition of gemtuzumab ozogamicin to induction or maintenance therapy failed to improve the complete response rate or overall survival in patients with acute myeloid leukemia.This randomized phase 3 clinical trial evaluated the potential benefit of the addition of gemtuzumab ozogamicin (GO) to standard induction and postconsolidation therapy in patients with acute myeloid leukemia. Patients were randomly assigned to receive daunorubicin (45 mg/m 2 per day on days 1, 2, and 3), cytarabine (100 mg/m 2 per day by continuous infusion on days 1-7), and GO (6 mg/m 2 on day 4; DA1GO) vs standard induction therapy with daunorubicin (60 mg/m 2 per day on days 1, 2, and 3) and cytarabine alone (DA). Patients who achieved complete remission (CR) received 3 courses of highdose cytarabine. Those remaining in CR after consolidation were randomly assigned to receive either no additional therapy or 3 doses of GO (5 mg/m 2 every 28 days). From

In a randomized trial of therapy for FMS-like tyrosine kinase-3 (FLT3) mutant acute myeloid leukemia in first relapse, 224 patients received chemotherapy alone or followed by 80 mg of the FLT3 inhibitor lestaurtinib twice daily. Endpoints included complete remission or complete remission with incomplete platelet recovery (CR/CRp), overall survival, safety, and tolerability. Correlative studies included pharmacokinetics and analysis of in vivo FLT3 inhibition. There were 29 patients with CR/CRp in the lestaurtinib arm and 23 in the control arm (26% vs 21%; P = .35), and no difference in overall survival between the 2 arms. There was evidence of toxicity in the lestaurtinib-treated patients, particularly those with plasma levels in excess of 20 μM. In the lestaurtinib arm, FLT3 inhibition was highly correlated with remission rate, but target inhibition on day 15 was achieved in only 58% of patients receiving lestaurtinib. Given that such a small proportion of patients on this trial achieved sustained FLT3 inhibition in vivo, any conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival of patients with FLT3 mutant acute myeloid leukemia in first relapse. This study is registered at www.clinicaltrials.gov as #NCT00079482.

Clofarabine is an active agent with acceptable toxicity in patients age 60 years or older with untreated AML who have at least one unfavorable prognostic factor. ORR did not seem affected by the presence of multiple unfavorable prognostic factors.

Less-intense remission induction regimens for adults with newly-diagnosed AML aim to reduce treatment-related mortality (TRM), here defined as death within 4 weeks after starting induction therapy. This assumes that TRM rates are similar to the 15-20% observed 20 years ago. Herein we test this assumption. We examined TRM rates in 1409 patients treated on SWOG trials and 1,942 patients treated at MD Anderson (MDA) from 1991-2009. 88% of the SWOG received “3+7” or regimens of similar intensity while 92% of the MDA patients received ara-C at 1.5-2.0g/m2 daily × 3-5 days + other cytotoxic agents. We examined the relationship between time and TRM rates after accounting for other covariates. TRM rates between 1991 and 2009 decreased from 18- 3% in SWOG and 16%- 4% at MDA. Multivariate analyses showed a significant decrease in TRM over time (p=0.001). The decrease in TRM was not limited to younger patients, those with a better performance status, or a lower WBC count. Though our observations are limited to patients treated with intensive therapy at SWOG institutions and MDA, the decrease in TRM with time emphasizes the problem with historical controls and could be considered when selecting AML induction therapy.

Key Points• Coexpression of NUP98/ NSD1 and FLT3/ITD in AML is associated with very low complete remission rates and poor survival.• It is the interaction between NUP98/NSD1 and FLT3/ITD that determines poor outcome in NUP98/NSD1-associated AML.NUP98/NSD1 has recently been reported in association with poor outcome in acute myeloid leukemia (AML). Previous studies also observed a high overlap between NUP98/ NSD1 and FLT3/ITD, raising the question as to whether the reported poor outcome is due to NUP98/NSD1 or caused by the co-occurrence of these 2 genetic lesions. We aimed to determine the prognostic significance of NUP98/NSD1 in the context of FLT3/ITD AML. A total of 1421 patients enrolled in 5 consecutive Children's Oncology Group/Children's Cancer Group and SWOG trials were evaluated. NUP98/NSD1 was found in 15% of FLT3/ ITD and 7% of cytogenetically normal (CN)-AML. Those with dual FLT3/ITD and NUP98/ NSD1 (82% of NUP98/NSD1 patients) had a complete remission rate of 27% vs 69% in FLT3/ ITD without NUP98/NSD1 (P < .001). The corresponding 3-year overall survival was 31% vs 48% (P 5 .011), respectively. In CN-AML, patients with concomitant NUP98/NSD1 and FLT3/ITD had a worse outcome than those harboring NUP98/NSD1 only. In multivariate analysis, the dual NUP98/NSD1 and FLT3/ITD remained an independent predictor of poor outcome, and NUP98/NSD1 without FLT3/ITD lost its prognostic significance. Our study demonstrates that it is the interaction between NUP98/NSD1 and FLT3/ITD that determines the poor outcome of patients with NUP98/NSD1 disease. (Blood. 2014;124(15):2400-2407

Myeloablative (131)I-anti-B1 RIT is relatively well tolerated when given with autologous stem-cell support and often results in prolonged remission durations with few late toxicities.