Prognostic Significance of Early Treatment Response in Pediatric Relapsed Acute Myeloid Leukemia: Results from the International Study Relapsed AML 2001/01.

Survival of pediatric relapsed AML is 20–30%. An important prognostic factor at relapse is duration of CR1, but the relevance of early treatment response at relapse has not been reported and is the subject of this report. In 2001 we initiated a prospective study for pediatric relapsed AML, excluding AML M3. FLAG is being used for 2 consecutive courses. Liposomal daunorubicin (DNX) as a potentially less cardiotoxic anthracycline was added or not in a 1:1 randomised fashion to the first course of FLAG. Efficacy data for both study arms are still blinded as the study is ongoing until early 2008. More than 500 patients from 13 groups worldwide were registered by April 2007. This analysis was confined to the 324 patients who are eligible, fully evaluable and relapsed before 1 January 2007, and of whom day 15 (from start of chemotherapy) and/or day “28” (obtained between days 28 and 42 from start of the 1^st course) bone marrow (BM) examinations are evaluable. Day 15 BM findings did not affect therapy, while more than 20% blasts on day “28” means the patient is off-protocol and eligible for more experimental therapy or no further treatment. Fifty-three percent of evaluable patients relapsed early (within one year from diagnosis). Absolute blast counts between day 15 and day “28” correlated significantly, but not very strongly (Rho 0.57, P<0.0001, n=211). The majority of patients with <20% blasts on day 15 also had <20% blasts on day “28” (143/158, 91%). However, 22 out of 53 (42%) of patients with ≥20% blasts on day 15 had less than 20% blasts on day “28”. In terms of prognostic significance, the day “28” BM results are more discriminative:

Taking duration of CR1 into account, patients with early relapse and BM blasts at day “28” of <20% had a comparable survival to those with late relapse and day “28” blasts of <20% (2-yr pOS 44% (34–55%) vs 53% (43–63%), p=.11). The survival of patients with BM blasts at day “28” ≥20% was poor for both early and late relapses (2-yr pOS 11% (1–21%) vs 21% (3–39%), p=.08). In a Cox regression analysis of survival, BM day 15 lost statistical significance (p=0.27), while BM blasts day “28” ≥20% (risk ratio 2.8, 95%-C.I. 1.7–4.7, p<.001) and early relapse (RR 1.52, 95%-C.I. 1.03–2.3, p=0.03) were each predictive for poor outcome after relapse. In conclusion, early treatment response is a strong and independent prognostic factor. A good early treatment response as determined on day “28” predicts a relatively favorable outcome in both early and late relapsed AML. Based on the day “28” bone marrow, patients that are very unlikely to be cured can be identified. These patients may be offered more experimental treatment. Alternatively, early treatment response may be useful for risk-group adapted therapy in relapsed AML.