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
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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.

Time Point 1Time Point 2Time Point 3
MRDDay 14 (Induction Day 14)Day 28 (RER) or 35 (SER) (End Induction)Day 84 (RER) or 119 (SER) (Interim Maintenance Day 28)
*Sensitivity < 0.01% 
“absolute” negative* 1/44 13/340 15/350 
low positive < 0.01% 1/27 8/89 5/50 
positive 0.01 %–0.1% 6/87 6/104 3/37 
positive 0.1%–1% 6/91 4/43 4/9 
positive > 1% 6/67 7/21 1/1 
total 20/316 45/597 30/448 
Time Point 1Time Point 2Time Point 3
MRDDay 14 (Induction Day 14)Day 28 (RER) or 35 (SER) (End Induction)Day 84 (RER) or 119 (SER) (Interim Maintenance Day 28)
*Sensitivity < 0.01% 
“absolute” negative* 1/44 13/340 15/350 
low positive < 0.01% 1/27 8/89 5/50 
positive 0.01 %–0.1% 6/87 6/104 3/37 
positive 0.1%–1% 6/91 4/43 4/9 
positive > 1% 6/67 7/21 1/1 
total 20/316 45/597 30/448 
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Topics:
acute lymphocytic leukemia, bone marrow, child, neoplasm, residual, medical oncology, methotrexate, adverse event, asparaginase, companion trial, cytarabine

Disclosures: Matloub:bristol-myers squibb: Employment. Gaynon:Enzon: Speakers Bureau.

Author notes

Corresponding author

2008, The American Society of Hematology
2008
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