Role of Etoposide in Combination with All-Trans Retinoic Acid in the Treatment of Elderly Patients with Acute Myeloid Leukemia and NPM1 Mutation

Rationale: In a previous randomized trial (AML HD98B) in elderly (>60 yrs) patients with AML (excluding APL), we could demonstrate that all-trans retinoic acid (ATRA) given as adjunct to intensive induction therapy with idarubicin, cytarabine and etoposide significantly improved outcome; this beneficial effect appeared to be restricted to patients having NPM1 mutation without concomitant FLT3-ITD (NPM1^mut/FLT3-ITD^neg). In our subsequent trial in elderly patients (AMLSG 06-04), all patients received ATRA with a similar backbone of chemotherapy, except that for induction therapy idarubicin was intensified and etoposide was omitted. NPM1^mut AML is associated with myelomonocytic/monocytic differentiation, and etoposide is believed to have a particular effect in these morphologic subtypes of AML.

Aims: To evaluate the impact of etoposide in combination with ATRA in elderly patients with AML exhibiting NPM1 mutation enrolled into two consecutive AMLSG protocols.

Methods: 171 patients with NPM1^mut AML were included in this retrospective analysis; 78 patients from trial AML HD98B (trial A; accrual from 1998 to 2004); and 95 patients from trial AMLSG 06-04 (trial B, 2004–2008). Twenty-nine of 78 (37%) patients and 87 of 93 (94%) received ATRA in trials A and B, respectively.

Results: Initial patient characteristics, such as median age (67.8 and 67.9 years for trial A and B, respectively), type of AML (de novo, secondary or therapy-associated), white blood cell count (WBC), LDH, and FLT3-ITD mutation status (41% and 47%), were not significantly different between the two cohorts. The rates of complete remission (CR) were 68% and 71% for NPM1^mut patients in trial A and B, respectively. Lower age and lower WBC counts were significantly associated with achievement of CR; study, treatment with ATRA, type of AML, and FLT3-ITD mutation status had no impact. Univariable survival analyses revealed no significant difference for the end points event-free (EFS), relapse-free (RFS) and overall survival (OS) between the two patient cohorts from trial A and B. However, when restricting the analysis to patients who had received ATRA, a significant better EFS (p=0.05) and RFS (p=0.03) was found for patients with the genotype NPM1^mut/FLT3-ITD^neg in trial A (that included etoposide) compared to trial B (in which etoposide was omitted); there was no difference in EFS (p=0.18) and RFS (p=0.09) for patients with the genotype NPM1^mut/FLT3-ITD^pos. In addition, no difference was seen either in patients with the genotype NPM1^mut/FLT3-ITD^pos or in patients with the genotype NPM1^mut/FLT3-ITD^neg in terms of OS mainly due to a high second CR rate in patients with the genotype NPM1^mut/FLT3-ITD^neg.

Conclusion: The data from this retrospective subgroup analysis suggest that etoposide in combination with ATRA may exert a beneficial synergistic effect in elderly patients with AML having NPM1 mutation without concurrent FLT3-ITD.