Douer, Dan

Key Points High WBC is an independent predictor of early HD in APL.

Purpose Extramedullary disease (EMD) at diagnosis in patients with acute myeloid leukemia (AML) has been recognized for decades. Reported herein are results from a large study of patients with AML who were treated in consecutive ECOG-ACRIN Cancer Research Group frontline clinical trials in an attempt to define the incidence and clinical implications of EMD. Methods Patients with newly diagnosed AML, age 15 years and older, who were treated in 11 clinical trials, were studied to identify EMD, as defined by physical examination, laboratory findings, and imaging results. Results Of the 3,522 patients enrolled, 282 were excluded, including patients with acute promyelocytic leukemia, incorrect diagnosis, or no adequate assessment of EMD at baseline. The overall incidence of EMD was 23.7%. The sites involved were: lymph nodes (11.5%), spleen (7.3%), liver (5.3%), skin (4.5%), gingiva (4.4%), and CNS (1.1%). Most patients (65.3%) had only one site of EMD, 20.9% had two sites, 9.5% had three sites, and 3.4% had four sites. The median overall survival was 1.035 years. In univariable analysis, the presence of any EMD ( P = .005), skin involvement ( P = .002), spleen ( P < .001), and liver ( P < .001), but not CNS ( P = .34), nodal involvement ( P = .94), and gingival hypertrophy ( P = .24), was associated with a shorter overall survival. In contrast, in multivariable analysis, adjusted for known prognostic factors such as cytogenetic risk and WBC count, neither the presence of EMD nor the number of specific sites of EMD were independently prognostic. Conclusion This large study demonstrates that EMD at any site is common but is not an independent prognostic factor. Treatment decisions for patients with EMD should be made on the basis of recognized AML prognostic factors, irrespective of the presence of EMD.

Abstract 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 20μM. 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.

Purpose To evaluate the efficacy and safety of arsenic trioxide monotherapy in patients with myelodysplastic syndromes (MDS). Patients and Methods Patients received arsenic trioxide (0.25 mg/kg/d) on 5 consecutive days per week for 2 weeks, followed by 2 weeks’ rest (one cycle). Two patient cohorts were established according to International Prognostic Scoring System risk category: lower-risk (low or intermediate-1) or higher-risk MDS (intermediate-2 or high). For lower-risk MDS, hematologic improvement (HI) was the primary response end point. For higher-risk MDS, additional end points included complete or partial remission. Based on the expected time to response, patients receiving two or more cycles were prospectively evaluated. Results Hematologic adverse events included neutropenia, thrombocytopenia, and febrile neutropenia. Two patients died during the study due to treatment-related toxicities. Most common grade 3/4 nonhematologic events were pneumonia, fatigue, hemorrhage, pain, and dyspnea. Among patients who received one or more doses (n = 70) or completed two or more cycles (n = 51), the HI rates were 34% and 39% in lower-risk patients, and 6% and 9% in higher-risk patients, respectively; the overall major HI rates were 20% and 22%. One higher-risk patient achieved a complete remission (3%). Major HIs were observed in all hematologic lineages; erythroid responses were the most common. Transfusion independence or reduction by ≥ 50% occurred in 33% of patients dependent on RBC transfusions. The overall median duration of HI was 6.8 months (range, 2 to 40 months). Conclusion Arsenic trioxide monotherapy has moderate activity against MDS, with a manageable adverse effect profile. The further study of arsenic trioxide in MDS, particularly in combination with other agents, is warranted.