Increased toxicity seen with high-dose daunorubicin induction in young AML patients – a Brazilian study

Rodrigo Portugal, and colleagues from the Federal University of Rio de Janeiro (UFRJ), retrospectively studied the outcomes of newly diagnosed Acute Myeloid Leukemia (AML) patients who were treated with High-Dose (HD) daunorubicin (90 mg/m²). The results of the study were published in Clinical Lymphoma, Myeloma & Leukemia in June 2017.²

In total, 12 AML patients (median age = 31 years, range 24–60) who were treated with HD daunorubicin (90 mg/m² on days 1–3) and intravenous cytosine arabinoside (200 mg/m² daily on days 1–7) between July 2010 – April 2015 at the University Hospital Clementino Fraga Filho and the UFRJ were analyzed. The outcomes of patients treated with HD daunorubicin were compared with patients (n = 14) who were treated with Low-Dose (LD) daunorubicin (45 or 60 mg/m²).

The key findings of the study were:

• Complete Remission (CR) rate in patients in the HD and LD daunorubicin groups; 66% (8/12) vs 64% (9/14), P = 1.0
• 30-day induction mortality rate in patients in the HD and LD daunorubicin groups; 25% vs 7.1%, P = 0.3
• Relapse rate in patients that achieved CR in the HD and LD daunorubicin groups; 37.5% vs 66.6%, P = 0.34
• A higher frequency of toxic Adverse Events (AEs) were seen in the HD group than the LD group:
  • Invasive fungal disease; 41.6% vs 0%, P = 0.012
  • Creatinine elevation; 41.6% vs 0%, P = 0.001
  • Abdominal pain; 33% vs 0%, P = 0.033
  • Intensive care unit admission; 33.3% vs 0%, P = 0.033
  • Four patients developed neutropenic enterocolitis in the HD group, P = 0.033

In summary, young AML patients receiving induction HD daunorubicin presented with greater incidences of toxic AEs than LD therapy, particularly gastrointestinal and invasive fungal disease.

This retrospective analysis suggests that there is increased toxicity in patients treated with HD daunorubicin. The authors noted that whilst daunorubicin induction dose should be more than 45 mg/m², according to their analysis there appears to be no clear benefit for a high 90 mg/m² dose.

 Abstract

The combination of an anthracycline and cytosine arabinoside has been the standard induction therapy for acute myeloid leukemia (AML) for more than three decades. The clinical benefit of intensification of daunorubicin dose to 90mg/m2 has been supported by randomized trials. Based on these promising results, in 2010 we changed our induction protocol of AML, increasing the dose of daunorubicin. Herein, we retrospectively analyzed the treatment outcome of patients treated with high-dose daunorubicin (90mg/m2 days 1-3) and cytosine arabinoside (200mg/m2/day continuous infusion days 1-7) compared with patients receiving 45-60mg/m2 of daunorubicin. Twenty-six previously untreated patients younger than 60 years of age were included. Twelve received high-dose daunorubicin (HD) and 14 the low-dose (LD). Seventeen patients were in CR after one induction cycle. There was no overall difference in complete remission rate between HD and LD (66% vs 64%; p=1.0). Thirty-day induction mortality was 15.3% overall, with a non-significant difference between groups (25% vs 7.1%; p=0.3). Relapses were observed in 9 (53%) patients: 3 (37.5%) in the HD group and in 6 (66.6%) in the LD group (P=0.34). Invasive fungal disease (41.6% vs 0%; P=0.012), creatinine elevation (P=0.001), abdominal pain (33% vs 0%; P=0.033) and need of intensive care unit admission (33.3 vs 0%; p=0.033) were more frequent in the HD group. Four patients in the HD group developed neutropenic enterocolitis (P=0.033). In conclusion, these data indicate that 90mg/m2 of daunorubicin increased the toxicity compared with lower doses.