The Number Of Peg-Asparaginase Doses Administered Is a Determinant Of Relapse Risk In Adult ALL Treated With a Pediatric-Like Regimen
Authors: Aldoss Ibrahim , Pullarkat Vinod , Martinez Daniel , Ji Lingyun , Douer Dan 
Published: October 2019

Abstract

Introduction
Asparaginase (ASN) is an essential drug in treating acute lymphoblastic leukemia (ALL). Pediatric studies have highlighted the significance of adequate and prolonged depletion of asparagine in preventing leukemia relapse. However, similar studies are lacking in adults as ASN is used less frequently mainly due to increased toxicities associated with age. The objective of this study was to evaluate the association between the number of pegaspargase (PEG-ASN) doses administered in a pediatric-inspired regimen and the risk of late leukemia relapse in adult ALL.

Methods
We reviewed patients with adult ALL who were treated at our institution with a modified BFM regimen (Douer D et al. Blood. 2012;120:1495) between 2004 and 2013. This regimen plan was to administer a total of 6 doses of PEG-ASN (2000 units/m2 per dose) administered through 2 cycles of induction, 4 cycles of consolidation and 2 cycles of delayed re-induction. The (PEG-ASN) dose was based on pharmacokinetic and asparagine depletion data previously established for adults (Douer D et al. Blood. 2007;109:2744-50). The study included patients aged 18 to 59 years who received all 8 cycles of the planned treatment courses and were started on POMP maintenance therapy. We excluded patients who relapsed, died, underwent HSCT or were lost follow up before starting maintenance therapy. Relapse was defined as recurrence of disease at any site (bone marrow, CNS, or extramedullary sites). The endpoint considered in the analyses was leukemia free survival (LFS). LFS was defined as the duration of time between the date when the maintenance therapy started and date of first relapse or date of death.

Results
We identified 60 patients who met the eligibility criteria. Median age was 32 years (range 18- 59) and 42 patients were males. Median presenting WBC at diagnosis was 7000/dL (range 1-350). Six patients had T-cell ALL and 37 patients were classified as high-risk (age > 35 years, initial WBC> 30,000/dL in B-cell ALL and > 100,000/dL in T-cell ALL, and/or unfavorable cytogenetics). The average number of PEG-ASN doses administered was 5 (range 0-6). Among all included patients, 43 had received all 6 doses, 2 received 5 doses, 4 received 4 doses, 5 received 3 doses, 3 received 2 doses, 2 received 1 dose and 1 received no PEG-ASN. Reasons for not completing all doses of PEG-ASN included anaphylaxis, pancreatitis, life-threatening thrombosis, and prolonged delay in treatment due to hyperbilirubinemia. The two- and five-year LFS from the time of starting maintenance therapy were 62±7% and 52±8%, respectively, for all patients. Patients risk category (standard risk vs. high risk) was not significantly associated with LFS. However, a significant association was found between the number of doses of PEG-ASN that patients received during the induction/consolidation cycles and LFS (Figure 1). Patients who received a higher number of doses of PEG-asp had significantly better LFS compared to those who received a lower number of doses (trend test: p=0.009).

Conclusion
In adult patients with ALL who had remained in first remission throughout the entire induction and consolidations period of a pediatric-like regimen, less prior exposure to PEG-ASN (<3 doses) was associated with increased late relapse risk after starting maintenance therapy. These results support the importance of ASN treatment in adult ALL.

Disclosures:
Douer: Sigma Tau: Membership on an entity’s Board of Directors or advisory committees.