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Anthracyclines used in the treatment of acute myelogenous leukemia (AML) inhibit the activity of the mammalian topoisomerase II (topo II) isoforms, topo II α and topo IIβ. In 230 patients with non-M3 AML who received frontline ara-C/daunorubicin we determined expression of topo IIα and topo IIβ by RT-PCR and its relationship to immunophenotype (IP) and outcomes. Treatment outcomes were analyzed by logistic or Cox regression. In 211 patients, available for analysis, topo IIα expression was significantly lower than topo IIβ (P

Effect of measurable (‘minimal’) residual disease (MRD) information on prediction of relapse and survival in adult acute myeloid leukemia

Purpose Younger patients with acute myeloid leukemia (AML) harboring NPM1 mutations without FLT3–internal tandem duplications (ITDs; NPM1-positive/FLT3-ITD–negative genotype) are classified as better risk; however, it remains uncertain whether this favorable classification can be applied to older patients with AML with this genotype. Therefore, we examined the impact of age on the prognostic significance of NPM1-positive/FLT3-ITD–negative status in older patients with AML. Patients and Methods Patients with AML age ≥ 55 years treated with intensive chemotherapy as part of Southwest Oncology Gorup (SWOG) and UK National Cancer Research Institute/Medical Research Council (NCRI/MRC) trials were evaluated. A comprehensive analysis first examined 156 patients treated in SWOG trials. Validation analyses then examined 1,258 patients treated in MRC/NCRI trials. Univariable and multivariable analyses were used to determine the impact of age on the prognostic significance of NPM1 mutations, FLT3-ITDs, and the NPM1-positive/FLT3-ITD–negative genotype. Results Patients with AML age 55 to 65 years with NPM1-positive/FLT3-ITD–negative genotype treated in SWOG trials had a significantly improved 2-year overall survival (OS) as compared with those without this genotype (70% v 32%; P < .001). Moreover, patients age 55 to 65 years with NPM1-positive/FLT3-ITD–negative genotype had a significantly improved 2-year OS as compared with those age > 65 years with this genotype (70% v 27%; P < .001); any potential survival benefit of this genotype in patients age > 65 years was marginal (27% v 16%; P = .33). In multivariable analysis, NPM1-positive/FLT3-ITD–negative genotype remained independently associated with an improved OS in patients age 55 to 65 years (P = .002) but not in those age > 65 years (P = .82). These results were confirmed in validation analyses examining the NCRI/MRC patients. Conclusion NPM1-positive/FLT3-ITD–negative genotype remains a relatively favorable prognostic factor for patients with AML age 55 to 65 years but not in those age > 65 years.

The aim of this study was to describe the fate of patients with newly diagnosed acute myeloid leukemia (AML) who did not achieve an initial remission while being treated on a contemporary cooperative group trial. We analyzed the outcome of patients entered into S0106, a recently reported cooperative group trial for patients with newly diagnosed AML. A total of 589 eligible patients was treated, of whom 150 (25%) did not achieve a remission while on study and were available for further analysis. The 4-year survival rate for the entire cohort of 150 patients was 23%. Among the 64 patients who received an allogeneic hematopoietic cell transplant, the 4-year survival rate was 48% compared with 4% for the 86 patients who did not undergo transplantation. Among those transplanted, we could not detect a difference in outcome according to remission status, donor source, type of preparative regimen, or cytogenetic risk category. More than 20% of patients with newly diagnosed AML who fail induction therapy can still be cured, particularly if they are able to receive an allogeneic hematopoietic cell transplant. These results suggest that early HLA typing and donor identification are important components of the initial therapy of AML.

Much recent attention has been given to evaluating surrogate endpoints for overall survival (OS) in various cancers. Valid surrogate endpoints for OS can reduce sample size, reduce follow-up duration, and decrease costs for trials. The US Food and Drug Administration (FDA) has approved new drugs in

Despite incremental progress over the last several decades, adult acute myeloid leukemia (AML) remains difficult to treat, and many patients experience therapeutic resistance, i.e. never attain a complete remission (CR) despite living long enough to have done so (i.e. are “primary refractory”)

Background: Therapeutic resistance, i.e. the failure to achieve complete remission (CR) or relapse from CR, is common in adult acute myeloid leukemia (AML). It is well recognized that the likelihood of complete remission (CR) and survival after receipt of therapy for relapsed/refractory AML (Òsalvage therapyÓ) varies widely with prior response duration being the primary predictor of both outcomes. One approach to salvage therapy trials would permit inclusion regardless of prior CR duration (CRD) given the possibility that a new drug might only be effective with longer CRD and that even with longer CRD standard therapies are hardly satisfactory. A second, more common approach relies on CRD to create a ÒhomogenousÓ population to facilitate data interpretation; yet, various arbitrary CRD cut-points have been used. This work examines whether a particular CRD might be used based on the relation between CRD and subsequent survival. Methods: We used information on patients with newly diagnosed AML other than acute promyelocytic leukemia receiving curative-intent treatment on 5 trials conducted by the Dutch-Belgian Cooperative Trial Group for Hematology/Oncology and the Swiss Group for Clinical Cancer Research (HOVON/SAKK; n=1,306) or on the SWOG S0106 trial (n=586). Failure was considered as completion of induction therapy without CR (CRD=0) or as relapse from CR. Survival after failure (SAF) was measured from the date of completing protocol induction therapy without report of CR or from the date of relapse, with SAF measured until the date of death from any cause with patients last known to be alive censored at the date of last contact. SAF was estimated using the Kaplan-Meier method. Cox regression was used to analyze the association between SAF and CR duration; the latter was modeled both quantitatively and categorically. Regression analyses with all three cohorts were stratified by cohort. Results: Among the 1,892 patients, 1,026 (54%) patients (median age: 48 years [range: 15-77 years]) failed induction therapy (n=430) or had a first CR duration of 2 years or less (n=596) and were included in our analyses. In the total patient cohort as well as in both treatment sites, longer CR duration was associated with longer SAF. In the total patient cohort, there was no evidence that the SAF for patients with first CR duration of 6 months or less was different or better than the SAF for patients who were primary refractory to induction therapy (see table). The same conclusion could be drawn when analyzing patients treated on HOVON/SAKK trials as separate cohort. In the SWOG cohort, there was no evidence that SAF with patients with first CR duration of 9 months or less was different or better than SAF of patients who were refractory to induction therapy. Conclusions: Limitations of this work include incomplete information about whether primary induction failures received 1 or 2 induction courses before failure was declared and about the therapy received after failure, as well as the presence of inter-cohort heterogeneity. Nonetheless, assuming SAF is a crucial endpoint and using data to establish its relation with CRD, our study indicates that patients who are primary refractory to 1-2 courses of intensive induction chemotherapy or who relapse within 6 months have distinctly different SAF than patients who relapse after a CR duration of more than 6 months. Regardless of whether these 2 subsets are deemed equally eligible for trials, our data could form the basis for rational stratification of patients enrolled on a trial for relapsed/refractory AML. Table 1: Hazard ratio (95% confidence interval) for Cox regression models for survival after failure (SAF). HOVON/SAKK(n=685) SWOG(n=341) All Patients(n=1,026) Failed Induction (Reference) (Reference) (Reference) CR 0-3 months 0.92 (0.69-1.23) 1.70 (0.96-3.02) 1.08 (0.83-1.40) CR 3-6 months 1.05 (0.83-1.32) 1.67 (1.07-2.62) 1.20 (0.98-1.47) CR 6-9 months 0.64 (0.51-0.81) 1.25 (0.84-1.87) 0.77 (0.63-0.94) CR 9-12 months 0.43 (0.31-0.59) 0.88 (0.59-1.30) 0.56 (0.43-0.72) CR 1-2 years 0.39 (0.30-0.52) 0.55 (0.36-0.83) 0.45 (0.35-0.56) Disclosures Petersdorf: Author deceased: Author recently deceased Other.