Impact Of Residual Disease On Survival In Pediatric Patients Receiving Allogeneic Hematopoietic Cell Transplantation For Acute Myeloid Leukemia In First Complete Remission

Residual disease (RD) detected in the marrow by multi-dimensional flow cytometry (MDF) is an important prognostic factor in patients with AML in first complete remission (CR1) treated with chemotherapy alone. We previously demonstrated in the Children’s Oncology Group (COG) AAML 03P1 trial, in a sample consisting predominantly of patients treated with chemotherapy alone, that the presence of RD at the end of the first course of induction (EOI1) confers a poor prognosis (Loken MR, et al. Blood 2012). This remains true even if the RD is subsequently cleared. Less is known about the influence of RD on the outcome of patients receiving allogeneic hematopoietic cell transplantation (HCT) in 1st CR. Adults with pre-transplant (PT) RD fare poorly (Walter RB, et al. Journal of Clinical Oncology 2011). The impact of PT-RD in pediatrics, however, has not yet been characterized.

We prospectively assessed the impact of PT-RD on transplant outcomes in patients enrolled on the COG AAML0531 (1022 patients) and AAML03P1 (339 patients) trials for de novo AML. In the 03P1 trial, patients in a morphologic remission, regardless of disease risk, with an HLA matched related donor (MFD) received HCT after the 3^rdcourse of chemotherapy (intensification 1). In the 0531 trial, HCT was performed depending on disease risk. AML was classified as low (inv(16), t(16;16), or t(8;21)), high (-7, -5/5q-, the presence of a high allelic ratio (>0.4) FLT3 ITD, or > 15% marrow blasts by morphology at EOI1) or intermediate risk (all others); those in morphologic remission with intermediate risk disease and an HLA matched family donor (MFD) and those with high-risk disease and any suitable donor underwent HCT after intensification 1. High dose busulfan and cyclophosphamide were recommended for conditioning and cyclosporine and methotrexate for graft versus host disease prophylaxis.

Of the patients who received HCT in CR1, 108 consented to and submitted specimens for PT RD evaluation by MDF. Of these 20 were RD positive (19%). The estimated OS at 3 years from transplant was 75.7%±9.3% for the MRD- patients and 47.0%±23.4% for the MRD+ patients (p=0.023). The cumulative incidences of relapse at 3 years were 30.0%±9.9% and 50.0%±23.3%, respectively (p=0.037). Given the impact of post induction RD in chemotherapy recipients, we further inquired whether in patients with RD at the EOI1, resolution of RD prior to HCT is associated with improved post transplant survival. 84 HCT recipients had MDF data for both the EOI1 and the pre-HCT time points; of them 33 were RD positive at EOI1 (39%), of which 12 remained positive prior to HCT (RD+/+); in the other 21 cases, the RD had cleared by the PT time point (RD+/-). In the remaining 51, RD was negative at both points (RD-/-). Actuarial OS at 3 years after HCT for the RD -/- patients and for the +/+ cohort was 74.1%±12.4% and 43.8%±31.4%, respectively (p=0.114); it was 76.2%±18.6% for the RD +/- patients (vs. -/-, p=0.999).

Our results indicate that in pediatric patients transplanted for AML in 1^st CR, PT-RD is associated with inferior survival; they also suggest that the magnitude of its effect appears to be less than reported in adults and raise the possibility that effective strategies for eliminating PT RD could be beneficial. Finally, our results suggest that in children receiving HCT, unlike those treated with chemotherapy alone, clearance of EOI1 RD may abrogate its prognostic significance, although our sample size was insufficiently large to definitely make this assessment. This hypothesis needs to be tested using a larger sample.

No relevant conflicts of interest to declare.