Predicting Survival Outcomes for Children With Down Syndrome and AML or MDS

Children with Down syndrome (DS) have a higher risk of developing acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML) than those without DS. Though these patients typically have a favorable event-free survival (EFS), they may experience treatment-related morbidity and mortality, complicating decisions about optimal treatment intensity.

In a report from the Children's Oncology Group (COG) AAML0431 trial published in Blood, Jeffrey W. Taub, MD, from the Children's Hospital of Michigan at Wayne State University, and co-authors examined treatment and survival trends, as along with the prognostic significance of minimal residual disease (MRD) levels, among patients with DS and AML (referred to as myeloid leukemia of DS [ML-DS]).

The AAML0431 study included 204 children (age range = 0-4 years) with a confirmed diagnosis of DS or DS mosaicism (the presence of typical chromosomes and an extra copy of chromosome 21) and AML (diagnosed according to the French-American-British classification, excluding promyelocytic leukemia; n=144) or myelodysplastic syndromes (MDS; with <30% blasts; n=60). Patients were enrolled between March 2007 and December 2011.

Children were excluded if they previously received chemotherapy, radiation, or any antileukemic therapy (except intrathecal cytarabine administered at diagnosis or as prior therapy for transient myeloproliferative disorders).

Treatment consisted of four cycles of induction therapy and two cycles of intensification therapy:

• induction cycles 1, 3, and 4: Continuous-infusion cytarabine 6.7 mg/kg per day for 4 days (96 hours), continuous-infusion daunorubicin 0.67 mg/kg for 24 hours every 4 days (96 hours), and oral 6-thioguanine 1.65 mg/kg twice daily for 4 days
• induction cycle 2: Cytarabine 100 mg/kg administered as a 3-hour infusion every 12 hours for 4 doses on days 1, 2, 8, and 9 with E. coli asparaginase 200 units/kg administered intramuscularly 3 hours after the last dose of cytarabine on days 2 and 9
• intensification cycles 1 and 2: Continuous-infusion cytarabine 3.3 mg/kg every 24 hours for 7 days (168 hours) and etoposide 4.2 mg/kg administered as a 1-hour infusion for 3 days

Cumulative chemotherapy doses were cytarabine 27,800 mg/m², daunorubicin 240 mg/m², and etoposide 750 mg/m².

At data cutoff (June 30, 2016) and after a median follow-up of 5.6 years (range = 0-8.7 years), 5-year EFS and overall survival were 91 percent and 93 percent, respectively. The cumulative incidence of relapse was 10 percent for patients with AML and 5.1 percent for patients with MDS (see TABLE for survival outcomes).

Most adverse events (AEs; 27.1% of total AEs and 66% of grade ≥3 AEs) occurred during induction cycle 2, when high-dose cytarabine was administered. The median time to absolute neutrophil count recovery (>1,000/μL) was also the longest during induction cycle 2 (median = 37 days; maximum = 67 days), and rates of hospitalization in the intensive care unit were highest during induction cycles 1 (6.9%) and 2 (7.0%).

Grade ≥3 febrile neutropenia was the most common AE and occurred most frequently during induction cycles 1 (27%) and 2 (29.7%). No life-threatening cardiac toxicities occurred, though seven grade ≥3 cardiac AEs were documented.

Treatment failure occurred in 20 patients, related to relapse (n=14), non-relapse death (n=3), secondary malignancies (n=2), and induction failure (n=1). Thirteen patients were taken off treatment during induction cycle 1 (n=4), induction cycle 2 (n=3), induction cycle 4 (n=2), and intensification cycle 1 (n=4).

Because MRD-positivity has been identified as a prognostic factor for patients with non-DS AML, Dr. Taub and researchers also assessed whether MRD levels could identify risk groups in patients with ML-DS. MRD data were available for 146 patients (71.6%), and detected in 21 patients (14.4%) following induction cycle 1. Those patients had significantly worse disease-free survival than those who were MRD-negative (76.2% vs. 92.7%; p=0.01). Patients who were MRD-positive were more likely to be male (p<0.001) and have isolated trisomies (other than trisomy 8; p=0.05).

Among MRD-negative patients, 8.3 percent (n=10/120) of those with evaluable response were not in complete response (CR) according to morphologic analyses, whereas 68.4 percent of MRD-positive patients (n=13) achieved CR. A morphologic bone marrow response after induction cycle 1 was associated with CR in 177 patients (87.2%), partial response in 15 (7.4%), and relapsed disease in 10 (4.9%).

"A comparison of marrow morphology and MRD analysis after induction 1 revealed that 23 of 139 patients (16.5%) classified by morphology would have been reclassified as positive or negative by MRD," the authors noted. "MRD therefore appears to be a more highly sensitive and objective indicator of response.

"The earlier use of high-dose cytarabine and reduction in daunorubicin dose was associated with better patient outcomes, compared with those seen in past COG trials," the authors concluded. "By identifying the appropriate patient population (e.g., MRD-negative after induction 1), a reduction in cytarabine dose intensity presents a logical approach to reduce potential toxicity, particularly infectious complications, in ML-DS patients."

The study is limited by its small patient population, particularly the number of patients with available MRD data, non-randomized design, and lack of validation of prognostic markers in an independent cohort.

Reference
Taub JW, Berman JN, Hitzler JK, et al. Improvement outcomes for myeloid leukemia of Down syndrome: a report from the Children's Oncology Group AAML0431 trial. Blood. 2017 April 7. [Epub ahead of print]