A B S T R A C T PurposeWe examined the outcome of patients with newly diagnosed acute promyelocytic leukemia (APL) treated with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) with or without gemtuzumab ozogamicin (GO) but without traditional cytotoxic chemotherapy. From February 2002 to March 2008 patients with APL were treated with a combination of ATRA plus ATO. The first cohort of 65 patients received ATRA and ATO (beginning on day 10 of ATRA). High-risk patients (WBCs Ն 10 ϫ 10 9 /L) received GO on the first day. From July 2007, the second cohort of 17 patients received ATRA and ATO concomitantly on day 1. They also received GO on day 1, if high risk, and if their WBC increased to more than 30 ϫ 10 9 /L during induction. Monitoring for PML-RARA fusion gene was conducted after induction and throughout consolidation and follow-up. Patients and Methods ResultsOverall, 74 patients achieved complete remission (CR) and one achieved CR without full platelet recovery after the induction, for a response rate of 92%. Seven patients died at a median of 4 days (range, 1 to 24 days) after inclusion in the study from disease-related complications. The median follow-up is 99 weeks (range, 2 to 282 weeks). Among the responding patients, three experienced relapse at 39, 52, and 53 weeks. Three patients died after being in CR for 14, 21, and 71 weeks, all from a second malignancy. The estimated 3-year survival rate is 85%. ConclusionThe combination of ATRA and ATO (with or without GO) as initial therapy for APL was effective and safe and can substitute chemotherapy-containing regimens.

A B S T R A C T PurposeThe current classification systems of myelodysplastic syndromes (MDS), including the International Prognostic Scoring System (IPSS), do not fully reflect the molecular heterogeneity of the disease. Molecular characterization may predict clinical outcome and help stratify patients for targeted therapies. Epigenetic therapy using decitabine, a DNA hypomethylating agent, is clinically effective for the treatment of MDS. Therefore, we investigated the association between DNA methylation and clinical outcome in MDS. Patients and MethodsWe screened 24 patients with MDS for promoter CpG island methylation of 24 genes and identified aberrant hypermethylation at 10 genes. We then performed quantitative methylation analyses by bisulfite pyrosequencing of the identified genes in 317 patient samples from three independent studies and assessed relations between methylation and clinical outcome. ResultsIn an initial training cohort of 89 patients with MDS, methylation frequencies of individual genes ranged from 7% to 70% and were highly concordant. Therefore, we defined a methylation z score based on all genes for each patient. We found that patients with higher levels of methylation, compared with patients with lower levels, had a shorter median overall survival (12.3 v 17.5 months, respectively; P ϭ .04) and shorter median progression-free survival (6.4 v 14.9 months, respectively; P ϭ .009). This methylation prognostic model was independent of age, sex, and IPSS group. Applied to two validation cohorts (228 patients), this model was confirmed as an independent prognostic predictor for survival. Although methylation at baseline did not correlate with clinical response to decitabine, we observed a significant correlation between reduced methylation over time and clinical responses. ConclusionDNA methylation predicts overall and progression-free survival in MDS. J Clin

Evidence suggests that the salvage therapy utilized for relapsed and refractory acute myelogenous leukemia (AML) should differ based on the duration of a patient's complete remission (CR), the principal predictor of outcome. While standard regimens have produced higher CR rates than investigational regimens, these rates have not translated into improved survival in patients with initial remission durations of Ͻ1 year. Accordingly, there is no need to give standard regimens to these patients who rather should receive investigational therapy once relapse is discovered. In contrast, in patients with initial remission durations of 1-2 years, standard regimens do increase survival compared to investigational regimens. A somewhat artificial distinction has been placed between phase I and phase II studies. The agents to be studied in phase II trials are many, but the patients are limited, so we need to be more innovative in our trial designs. One such proposal, utilizing a Bayesian selection design which calls for randomizing a small number of patients among several investigational treatments, will be discussed. Leukemia (2000) 14, 476-479.

Gemtuzumab ozogamicin (GO) is a chemotherapeutic agent that consists of a humanized anti‐CD33 antibody (hP67.6) linked to N‐acetyl‐γ calicheamicin 1,2‐dimethyl hydrazine dichloride, a potent enediyne antitumor antibiotic. GO was approved conditionally by the Federal Drug Administration in May 2000 as single‐agent therapy for first recurrence of acute myeloid leukemia (AML) in a subset of older patients. Data on studies in AML with GO‐based regimens have been reported rapidly in addition to new observations on the target antigen, CD33. These data indicate promising new areas of investigation with GO, including its application as maintenance therapy in patients with AML and as an induction and/or maintenance agent in patients with acute promyelocytic leukemia;, and they also have highlighted challenges in the development of GO, particularly its association with hepatic venoocclusive disease. In vitro data on the mechanism of action of GO may be particularly helpful in the design of future clinical studies. Cancer 2003. © 2003 American Cancer Society.