Bone Marrow (BM) Minimal Residual Disease (MRD) at End of Induction and Interim Maintenance Is Highly Predictive of Outcome in Children with Standard Risk (SR) Acute Lymphoblastic Leukemia (ALL) Treated on the Children's Oncology Group Study 1991

Three thousand fifty four children with NCI SR ALL were enrolled on CCG-1991; 2075 eligible patients were randomized and began treatment with intrathecal cytarabine, vincristine (V), dexamethasone (DX), and pegylated asparaginase (ASP). Bone marrow status was assessed at Day 7 and 14, and 28 of Induction. Slow early responders (SER's) (Day 7/14 M3-M3, or M3-M2; and M2 at Day 28 Induction) received rescue daunorubicin and were assigned to augmented BFM therapy (N Engl J Med 1998; 338:1663). Other patients were designated rapid early responders (RER's) and randomly allocated to V/ intravenous methotrexate versus oral 6MP/oral methotrexate, and DX pulses in months 3–4 and 7–8 of therapy and single or double delayed intensification. The 5-year EFS for RER's and SER's was 90.5% (SE ± 1.0%) and 84.7% (SE = ±3.7%). Eight hundred three patients elected to participate in a companion study of minimal residual disease (MRD), which was successfully performed on BM samples of 750 patients (93.4%). Out of 1362 BM submitted samples, 1360 were successfully tested. MRD was assessed by real-time quantitative PCR of clone-specific immunoglobulin heavy chain, immuno-globulin kappa deleting element, and T-cell receptor gene rearrangements on Day 14 Time Point (TP #1) for patients not achieving M1 status at Day 7, end Induction (TP #2) and Day 84 (RER's) or Day 119 (SER's) (TP #3), i.e., Day 28 of Interim Maintenance). Various levels of MRD positivity were explored for prognostic significance (see Table). At TP's 1, 2, and 3, 14%, 57%, and 78% had undetectable MRD with sensitivity of 0.01% or better. At the three time points patients with detectable MRD were 2.7 to 4.3 times more likely to fail than patients with undetectable MRD. TP #1, however, unlike TP #2 and TP #3 was not predictive of EFS in our study. Patients who had MRD > 0.01% at TP#1 had a much lower EFS at 4 years if at TP #3 MRD persisted at > 0.01% vs ≤ 0.01% (78 ± 0.1% vs 94 ± 0.05%, p = 0.01). We assessed MRD by PCR at three TP's in a homogeneous population of children with SR ALL receiving V/ DX/ASP. At end of induction, 57% of patients were MRD negative but still accrued 1/3 of adverse events.