Maintenance therapy with decitabine in younger adults with acute myeloid leukemia in first remission: a phase 2 Cancer and Leukemia Group B Study (CALGB 10503)

PURPOSE: The Cancer and Leukemia Group B conducted parallel phase I trials of cytarabine, daunorubicin, and etoposide (ADE) with or without PSC-833 (P), a modulator of p-glycoprotein–mediated multidrug resistance.PATIENTS AND METHODS: One hundred ten newly diagnosed patients ≥ 60 years of age with de novo acute myeloid leukemia (AML) were treated. All patients received cytarabine by continuous infusion for 7 days at 100 mg/m2/d. The starting dose of daunorubicin was 30 mg/m2/d for 3 days. Etoposide was administered at a dose of 100 mg/m2/d for 3 days, except in the last cohort administered ADEP, who received 60 mg/m2. PSC-833 was given intravenously with a loading dose of 1.5 mg/kg over 2 hours and a simultaneous continuous infusion of 10 mg/kg/d continued until 24 hours after the last dose of daunorubicin or etoposide.RESULTS: There was no toxicity attributed to the PSC-833. Dose-limiting toxicity was primarily gastrointestinal (diarrhea, mucositis in the ADEP group). The estimated maximum-tolerated doses, calculated using a logistic regression model, were daunorubicin 40 mg/m2/d for 3 days with etoposide 60 mg/m2for 3 days in the ADEP group and daunorubicin 60 mg/m2/d for 3 days and etoposide 100 mg/m2/d for 3 days in the ADE group. Twenty-one (48%) of 44 patients achieved complete remission with ADE, compared with 29 (44%) of 66 patients treated with ADEP.CONCLUSION: It is necessary to decrease the doses of daunorubicin and etoposide when they are administered with PSC-833, presumably because of the effect of the modulator on the pharmacokinetics of these agents. A phase III trial comparing the regimens derived from this phase I trial has recently begun.

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Patients With Acute Myeloid Leukemia and RAS Mutations Benefit Most From Postremission High-Dose Cytarabine: A Cancer and Leukemia Group B Study

Journal of Clinical Oncology ◽

10.1200/jco.2007.14.0418 ◽

2008 ◽

Vol 26 (28) ◽

pp. 4603-4609 ◽

Cited By ~ 94

Author(s):

Andreas Neubauer ◽

Kati Maharry ◽

Krzysztof Mrózek ◽

Christian Thiede ◽

Guido Marcucci ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

High Dose ◽

Relapse Risk ◽

Ras Mutations ◽

High Dose Cytarabine ◽

Group B ◽

The Impact ◽

Leukemia Group ◽

Acute Myeloid

Purpose RAS mutations occur in 12% to 27% of patients with acute myeloid leukemia (AML) and enhance sensitivity to cytarabine in vitro. We examined whether RAS mutations impact response to cytarabine in vivo. Patients and Methods One hundred eighty-five patients with AML achieving complete remission on Cancer and Leukemia Group B study 8525 and randomly assigned to one of three doses of cytarabine postremission were screened for RAS mutations. We assessed the impact of cytarabine dose on cumulative incidence of relapse (CIR) of patients with (mutRAS) and without (wild-type; wtRAS) RAS mutations. Results Thirty-four patients (18%) had RAS mutations. With 12.9 years median follow-up, the 10-year CIR was similar for mutRAS and wtRAS patients (65% v 73%; P = .31). However, mutRAS patients receiving high-dose cytarabine consolidation (HDAC; 3 g/m2 every 12 hours on days 1, 3, and 5 or 400 mg/m2/d × 5 days) had the lowest 10-year CIR, 45%, compared with 68% for wtRAS patients receiving HDAC and 80% and 100%, respectively, for wtRAS and mutRAS patients receiving low-dose cytarabine (LDAC; 100 mg/m2/d × 5 days; overall comparison, P < .001). Multivariable analysis revealed an interaction of cytarabine dose and RAS status (P = .06). After adjusting for this interaction and cytogenetics (core binding factor [CBF] AML v non-CBF AML), wtRAS patients receiving HDAC had lower relapse risk than wtRAS patients receiving LDAC (hazard ratio [HR] = 0.67; P = .04); however, mutRAS patients receiving HDAC had greater reduction in relapse risk (HR = 0.28; P = .002) compared with mutRAS patients treated with LDAC. Conclusion AML patients carrying mutRAS benefit from higher cytarabine doses more than wtRAS patients. This seems to be the first example of an activating oncogene mutation favorably modifying response to higher drug doses in AML.

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Prognostic Importance ofMN1Transcript Levels, and Biologic Insights FromMN1-Associated Gene and MicroRNA Expression Signatures in Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study

Journal of Clinical Oncology ◽

10.1200/jco.2008.20.6110 ◽

2009 ◽

Vol 27 (19) ◽

pp. 3198-3204 ◽

Cited By ~ 109

Author(s):

Christian Langer ◽

Guido Marcucci ◽

Kelsi B. Holland ◽

Michael D. Radmacher ◽

Kati Maharry ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Expression Profiles ◽

Microrna Expression ◽

Wild Type ◽

Prognostic Importance ◽

Group B ◽

Leukemia Group ◽

Tandem Duplications ◽

Acute Myeloid

PurposeTo determine the prognostic importance of the meningioma 1 (MN1) gene expression levels in the context of other predictive molecular markers, and to derive MN1 associated gene– and microRNA–expression profiles in cytogenetically normal acute myeloid leukemia (CN-AML).Patients and MethodsMN1 expression was measured in 119 untreated primary CN-AML adults younger than 60 years by real-time reverse-transcriptase polymerase chain reaction. Patients were also tested for FLT3, NPM1, CEBPA, and WT1 mutations, MLL partial tandem duplications, and BAALC and ERG expression. Gene- and microRNA-expression profiles were attained by performing genome-wide microarray assays. Patients were intensively treated on two first-line Cancer and Leukemia Group B clinical trials.ResultsHigher MN1 expression associated with NPM1 wild-type (P < .001), increased BAALC expression (P = .004), and less extramedullary involvement (P = .01). In multivariable analyses, higher MN1 expression associated with a lower complete remission rate (P = .005) after adjustment for WBC; shorter disease-free survival (P = .01) after adjustment for WT1 mutations, FLT3 internal tandem duplications (FLT3-ITD), and high ERG expression; and shorter survival (P = .04) after adjustment for WT1 and NPM1 mutations, FLT3-ITD, and WBC. Gene- and microRNA-expression profiles suggested that high MN1 expressers share features with high BAALC expressers and patients with wild-type NPM1. Higher MN1 expression also appears to be associated with genes and microRNAs that are active in aberrant macrophage/monocytoid function and differentiation.ConclusionMN1 expression independently predicts outcome in CN-AML patients. The MN1 gene- and microRNA-expression signatures suggest biologic features that could be exploited as therapeutic targets.

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