Current treatment regimens for childhood ALL have resulted in long-term event-free survival (EFS) of approximately 80%. On DFCI ALL Consortium Protocol 05-001, patients (pts) with newly diagnosed ALL aged 1-18 years (yrs) who achieved complete remission (CR) were eligible to participate in a randomized comparison of native E.coli asparaginase (ASP) given intramuscularly (IM) and PEG ASP, the polyethylene glycol conjugate of E.coli ASP, given intravenously (IV). The objective was to compare the serum ASP activity (SAA), toxicity, and EFS of the two ASP preparations. An intensified consolidation regimen for VHR pts, including B-ALL pts with high end-induction minimal residual disease (MRD), was also evaluated.

Methods

All pts received 1 dose of PEG ASP (2500 IU/m2) during the 4-week (wk) multiagent induction phase. After CR was achieved, final risk group was assigned based on age, presenting WBC, CNS status, cytogenetics and end-induction MRD (assessed by PCR). All T-ALL pts were considered HR. Pts were considered VHR if they met one of the following criteria: i) B-ALL with high end-induction MRD; or ii) adverse cytogenetics (MLL gene rearrangement or hypodiploidy). BCR-ABL positive pts began daily imatinib at Day 18 and were allocated to allogeneic transplant in 1st CR. Beginning at wk 7, pts began the consolidation phase including 30 wks of ASP, either IM E.coli ASP 25000 IU/m2 weekly or IV PEG 2500 IU/m2 every 2 wks. In addition, SR pts received every 3-wk cycles with vincristine, dexamethasone, 6MP and low-dose methotrexate (mtx) during consolidation; HR pts received doxorubicin (cumulative dose 300 mg/m2) with dexrazoxane instead of mtx during this phase. VHR pts received 2 additional cycles beginning at week 7 (cyclophosphamide/low-dose araC/6-MP and then high-dose araC/etoposide/dexamethasone), followed by the HR consolidation phase. Continuation phase was identical for all pts. Total duration of therapy was 25 months. Serum samples were obtained every 6 wks just prior to an ASP dose to measure SAA. EFS rates were calculated from date of registration, except for EFS by randomized arm, risk group, and end-induction MRD, which were calculated from time of randomization.

Results

Between 2005-2010, 551 evaluable pts enrolled, of whom 526 (95%) achieved CR. 463 pts participated in the ASP randomization. Median nadir SAA was significantly higher with IV PEG than with IM E.coli ASP,(Table 1) with more IV PEG-randomized pts achieving nadir SAA ≥ 0.1 IU/mL (p<0.01 at each time point). There was no significant difference in ASP-related allergy (p=0.36) and pancreatitis (p=0.54) between the two arms, and a trend toward more thrombotic events with E.coli ASP (p=0.07). With 4.5 yrs median follow-up, the 4-yr EFS for all 551 pts was 86% [95% CI 82-88%]. Outcome by pt characteristics are displayed in Table 2. The 4-yr EFS for B-ALL pts with high end-induction MRD was 77% [95% CI 60-88%]. There was no difference in EFS between the randomized arms (p=0.31).

Table 1

ASP-related Toxicity and Nadir Serum ASP activity (NSAA) during Consolidation

IM E.coli (N=231)IV PEG (N=232)p-value
Allergy 9% 12% 0.36 
Pancreatitis 9% 11% 0.54 
Thrombosis 11% 6% 0.07 
Median NSAA (wk 11 of Consolidation) 0.096 IU/mL 0.758 IU/mL <0.01 
% pts with  NSAA ≥ 0.1 IU/mL (wk  11 of Consolidation) 46% 99% <0.01 
IM E.coli (N=231)IV PEG (N=232)p-value
Allergy 9% 12% 0.36 
Pancreatitis 9% 11% 0.54 
Thrombosis 11% 6% 0.07 
Median NSAA (wk 11 of Consolidation) 0.096 IU/mL 0.758 IU/mL <0.01 
% pts with  NSAA ≥ 0.1 IU/mL (wk  11 of Consolidation) 46% 99% <0.01 
View Large
Table 2

Outcome by Patient Characteristics

 N4-yr EFSp-value
All eligible pts 551 86%  
Risk Group    
SR 268 94% <0.01 
HR 190 87%  
VHR 52 79%  
Age    
1-10 yrs 398 88% 0.06 
≥10 yrs 153 80%  
Phenotype    
B-precursor 482 85% 0.58 
T-ALL 69 88%  
End-Induction MRD (B-ALL only)    
Low (<0.001) 338 91% 0.03 
High (≥0.001) 40 77%  
Cytogenetics    
Normal 131 87% 0.92 
High Hyperdiploid (HeH) 145 89% 0.14 
HeH with trisomies 4 + 10 88 95% 0.07 
TEL/AML1 97 98% <0.01 
Hypodiploid (<45) 8 88% 0.91 
MLL-R 10 60% <0.01 
BCR-ABL 16 69% 0.01 
ASP Randomization    
E.coli ASP 231 90% 0.31 
PEG 232 92%  
 N4-yr EFSp-value
All eligible pts 551 86%  
Risk Group    
SR 268 94% <0.01 
HR 190 87%  
VHR 52 79%  
Age    
1-10 yrs 398 88% 0.06 
≥10 yrs 153 80%  
Phenotype    
B-precursor 482 85% 0.58 
T-ALL 69 88%  
End-Induction MRD (B-ALL only)    
Low (<0.001) 338 91% 0.03 
High (≥0.001) 40 77%  
Cytogenetics    
Normal 131 87% 0.92 
High Hyperdiploid (HeH) 145 89% 0.14 
HeH with trisomies 4 + 10 88 95% 0.07 
TEL/AML1 97 98% <0.01 
Hypodiploid (<45) 8 88% 0.91 
MLL-R 10 60% <0.01 
BCR-ABL 16 69% 0.01 
ASP Randomization    
E.coli ASP 231 90% 0.31 
PEG 232 92%  
View Large
Conclusion

Overall EFS on Protocol 05001 compares favorably with previously published outcomes for pediatric ALL. Intensified consolidation improved outcome for B-ALL pts with high end-induction MRD. Relatively favorable outcomes were also observed in other high-risk pt subsets, including older children/adolescents and pts with T-ALL. We have demonstrated that IV PEG is as effective as and no more toxic than weekly IM E.coli ASP in children and adolescents with ALL.

Disclosures:

Silverman:Sigma Tau Pharmaceuticals: Consultancy. Andrew:Sigma Tau Pharmaceuticals: Consultancy. Neuberg:Synta Pharmaceuticals: Trust owns stock; I am a Trustee Other. Sallan:Sigma Tau Pharmaceuticals: Consultancy.

Topics:
6-mercaptopurine, adolescent, adult t-cell lymphoma/leukemia, asparaginase, bcr-abl tyrosine kinase, brachial plexus neuritis, burkitt's lymphoma, child, complete remission, cyclophosphamide

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2013 by The American Society of Hematology
2013
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