Abstract
Abstract 321
The DFCI-ALL Consortium Protocol 00-01 aimed to determine the relative efficacy and toxicity of 1) dexamethasone (DEX) vs. prednisone (PRED) and 2) asparaginase (ASP) with individualized dosing (ID) based on pharmacokinetic measurements vs. standard fixed dosing (FD) based on body surface area, in the treatment of children with newly diagnosed acute lymphoblastic leukemia (ALL).
Between 2000 and 2004, 492 eligible patients (pts) ages 1-18 years (yrs) with newly diagnosed ALL enrolled on Protocol 00-01 from 10 institutions. 282 pts were standard risk (SR) and 210 high risk (HR). Post-induction treatment for all patients included 30 weeks of intramuscular E. coli ASP (beginning at week 7) and vincristine/corticosteroid pulses every 3 weeks for 24 months. Pts who achieved complete remission (CR) were eligible for two randomized comparisons: 1) Steroids: Pts were randomized to receive either DEX or PRED given as 5-day pulses every 3-weeks, and 2) ASP: Pts were randomized to receive either FD (25,000IU/m2) or ID (starting dose 12,500 IU/m2) for 30 weeks. Nadir serum ASP activity (NSAA) was assessed every 3 weeks, and ASP doses on the ID arm were adjusted to maintain NSAA between 0.10-0.14 IU/mL. NSAA was assayed centrally by a validated biochemical assay.
473 pts (96%) achieved CR. With a median follow-up of 4.9 years, the 5-year event-free survival (EFS) ± standard error for all 492 pts was 80 ± 2% and overall survival (OS) was 91 ± 1%.
408/473 pts (86%) participated in the steroid randomization (DEX: 201, PRED: 207). Pts randomized to DEX had 5-yr EFS of 90 ± 2% compared with 81 ± 3% for PRED (p=0.01) [Table I]. For pts 10-18 yrs of age, there was a significant increase in the rate of osteonecrosis (ON) with DEX, with 5-yr cumulative incidence (CI) of 23% compared with 4.7% for PRED (p=0.02). There was no difference in the 5-yr CI of ON based on steroid type in pts 1-10 yrs of age (DEX: 2.6% vs. PRED: 4.3%, p=0.43). Fractures were also more common in pts 10-18 yrs of age randomized to DEX (p=0.06), but not in younger pts (p=0.25). Infection (positive blood culture or radiographic evidence of invasive fungal disease) developed in 38 pts (18.8%) randomized to DEX compared with 22 pts (10.6%) randomized to PRED (p=0.03). There was no difference in remission death rate based on steroid randomization (DEX 0% vs. PRED 2%, p=0.5).
5-year EFS by Randomized Arm
| . | Steroid . | ASP . | ||
|---|---|---|---|---|
| DEX (N) . | PRED (N) . | ID ASP (N) . | FD ASP (N) . | |
| Overall | 90 ± 2% (201) | 81 ± 3% (207) | 90 ± 2% (189) | 82 ± 3% (195) |
| SR | 89 ± 3% (114) | 84 ± 4% (121) | 89 ± 3% (115) | 86 ± 4% (110) |
| HR | 91 ± 4% (87) | 78 ± 5% (86) | 93 ± 3% (74) | 78 ± 5% (85) |
| 1-10 yrs | 91 ± 3% (153) | 82 ± 3% (164) | 90 ± 3% (147) | 85 ± 3% (151) |
| 10-18 yrs | 88 ± 5% (48) | 77 ± 6% (43) | 90 ± 5% (42) | 72 ± 7% (44) |
| . | Steroid . | ASP . | ||
|---|---|---|---|---|
| DEX (N) . | PRED (N) . | ID ASP (N) . | FD ASP (N) . | |
| Overall | 90 ± 2% (201) | 81 ± 3% (207) | 90 ± 2% (189) | 82 ± 3% (195) |
| SR | 89 ± 3% (114) | 84 ± 4% (121) | 89 ± 3% (115) | 86 ± 4% (110) |
| HR | 91 ± 4% (87) | 78 ± 5% (86) | 93 ± 3% (74) | 78 ± 5% (85) |
| 1-10 yrs | 91 ± 3% (153) | 82 ± 3% (164) | 90 ± 3% (147) | 85 ± 3% (151) |
| 10-18 yrs | 88 ± 5% (48) | 77 ± 6% (43) | 90 ± 5% (42) | 72 ± 7% (44) |
384/473 pts (81%) participated in the ASP randomization (FD: 195, ID: 189). Pts randomized to ID had superior EFS with 5-yr EFS of 90 ± 2% compared with 82 ± 3% for FD (p=0.04) [Table I]. There was no difference between the two arms in the frequency of ASP-related allergy (p=0.46), pancreatitis (p=0.66) or thrombosis (p=0.77). There was also no difference by treatment arm in the proportion of pts able to complete at least 25 weeks of ASP (FD: 88% vs. ID: 87%, p=0.76). There was no difference between the two arms in the proportion of pts with non-detectable NSAA, although fewer pts on the ID arm had high NSAA (>0.14 IU/mL). On multivariable analysis, both DEX and ID ASP were independent predictors of favorable outcome (hazard ratio 0.49 for DEX, p=0.02; hazard ratio 0.52 for ID, p=0.04), with no indication of an interaction. Only 5/92 (5%) pts randomized to both DEX and ID ASP experienced an event.
DEX was associated with superior EFS, but also more bone and infectious toxicities, especially in older children/adolescents. Future studies should focus on minimizing DEX toxicity in older pediatric pts without compromising efficacy. ID of ASP was feasible and was associated with superior EFS. The improved EFS with ID was not due to a reduction in ASP-related toxicity or improved tolerability, but was associated with a reduction in the proportion of pts with high NSAA.
Supko:Enzon Inc.: Research Funding. Sallan:Enzon Inc.: Research Funding; Enzon Inc.: Contributed to support of an investigator meeting.
Author notes
Asterisk with author names denotes non-ASH members.
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