Severe Toxicities During Pediatric Acute Myeloid Leukemia Chemotherapy: A Report From the Children's Oncology Group.

Treatment of children with acute myeloid leukemia (AML) is associated with considerable toxicity. Children's Oncology Group (COG) AAML0531 trial adopted a modified AML Medical Research Council backbone and reviewed adverse event reports in real time to maximize accurate toxicity data. As of March 31, 2010, AAML0531 had randomized 968 patients with de novo AML to gemtuzumab ozogamicin (GMTZ) versus no GMTZ. Accurate description of toxicities with the backbone regimen as well as increment toxicities of new agents is important to optimize supportive care. Objectives were to describe hepatic, cardiac and infectious toxicities and duration of neutropenia in all patients, and to compare toxicities between treatment arms.

AAML0531 included those ≥ 1 month to ≤ 30 years with de novo AML and used a 5 cycle chemotherapy regimen: Induction (Ind) I and II: cytarabine, daunorubicin, and etoposide (ADE 10+3+5 and 8+3+5); Intensification (Int) I: cytarabine and etoposide; Int II: mitoxantrone and high-dose cytarabine; and Int III: high-dose cytarabine and L'asparaginase. Subjects were randomized to receive or not receive GMTZ 3 mg/m² during Ind I and Int II.

Common Terminology Criteria for Adverse Events v3.0 toxicities were collected prospectively. Hepatic (ALT, bilirubin and veno-occlusive disease (VOD)), cardiac (left ventricular systolic dysfunction (LVSD)) and infection (sterile site bacterial and fungal) toxicities were targeted. All grades of cardiac and VOD toxicities were captured; all other severe (≥ grade 3) toxicities were recorded. Cumulative incidence (CI) of toxicities was calculated only during protocol chemotherapy. Duration of neutropenia was reported from beginning of cycle to absolute neutrophil recovery ≥ 500/uL for patients alive during the cycle.

Table describes the prevalence of severe (≥ grade 3) toxicities and illustrates that severe high ALT occurred in 3–10%, high bilirubin was less common and VOD was reported in ≤ 1% of cycles. Severe LVSD also was rare although compliance with suggested cardiac monitoring ranged from 50–80% per course of treatment. In terms of grade 1 or 2 LSVD there were no differences in any course except for Int II where grade 1 or 2 LVSD was higher with GMTZ (8.0% versus 2.4%; P<.05). Severe sterile bacterial infections were very common occurring in about 30% during Ind I and II, 45% during Int I and 60% during Int II and III.

The eight month CI of severe high ALT was 19±4%, hyperbilirubinemia was 10±3%, and VOD was 1±1%. CI of severe elevations in ALT were near significantly more common with GMTZ (22±5% versus 16±5%, P=0.053). Severe LVSD CI was 4±2%, sterile site bacterial infection CI was 82±4% and sterile site microbiologically documented fungal infections CI was 14±3%. CI of severe hyperbilirubinemia, VOD, LVSD and infections were not significantly different with GMTZ.

The median (range) duration of neutropenia of Ind I and II in the no GMTZ arm were 30 (3-75) and 28 (1-61) days while for Int I, II and III were 27 (1-53), 37 (6-92) and 39 (16-91) days respectively. Administration of GMTZ did not significantly prolong neutropenia. There was no difference in toxic mortality by GMTZ during Ind I or across all courses of chemotherapy.

The COG AML0531 backbone regimen is associated with significant toxicities: 19% of patients have severe elevations in ALT and 10% have severe hyperbilirubinemia. VOD is rare and occurs in 1%. Sterile site invasive infections are very common, particularly during high dose cytarabine. Sterile site microbiologically documented fungal infections occurs in 14% in spite of current supportive care practices. GMTZ contributes to increased high ALT and more grade 1 or 2 LVSD, both of which are of questionable clinical significance. Understanding these toxicities is important as this backbone will be carried into future studies of AML. Decreasing both bacterial and fungal infections will be important supportive care initiatives.

Smith:Pfizer, Inc: Member, Medical Advisory Committee (for bosutinib, not GO).