Abstract

Introduction

L-asparaginase therapy results in systemic depletion of antithrombin (AT) and fibrinogen (FG), resulting in thrombotic (TE) and hemorrhagic events (HE). Prophylactic correction of coagulation disturbances have been inconclusive with regard to cost effectiveness, and specifically cost effectiveness of antithrombin concentrate (ATC) replacement has not been evaluated. (Abbott et al, 2009, Mitchell et al, 2003). Currently, AT repletion is recommended for levels less than 60%. (Stock et al, 2012) Several treatment protocols with distinctly different L-asparaginase (LAS) or pegaspargase (PEG) doses complicate the frequency and intensity of ATC replacement. We carried out this study to evaluate the cost effectiveness of ATC replacement, based on our institutional practice.

Methods

This single center, retrospective, observational study was approved by the Institutional Review Board and conducted at Mayo Clinic, Rochester, MN. Consecutive adult patients with a confirmed diagnosis of ALL receiving LAS or PEG between January 2000 and October 2012 were evaluated. Patients with hereditary or acquired thrombophilias or pre-existing TE or HE, were excluded. Per institutional guidelines, ATC was administered if levels were less than 70%. The Centers for Medicare & Medicaid (CMS) single drug historical pricing guide was utilized for 2000-2004. ATC cost beginning January 1, 2005, was derived from the CMS average sales price, reported quarterly. To adjust for price differences due to regimen utilization trends, each dose was also calculated at the final 2012 cost of 3.05/unit. ATC repletion practices and estimated expenditures were compared between regimens.

Results

Fifty four patients were treated with LAS or PEG containing regimens. Of these, 47 (87%) received ATC. Twenty-eight patients received LASP, 22 received PEGASP and 4 received both. Distribution across protocols was; CALGB 9111 (n=20, Larson et al, 1998), E2993 (n=13, Goldstone et al, 2008), C10403 (n=9, NLM: NCT00558519), CCG 1941 (n=7, Gaynon et al, 2006) and Augmented HyperCVAD (n=5, Faderl et al, 2005). PEG and LAS dosing schemes are outlined in table 1 

Table 1

Regimen Dosing Schemes

Regimen Phase or Duration Dose (Cycle days) Patients
n (%) 
Median Doses/Pt  
Augmented Hyper-CVAD (AHC) 8 cycles LAS 20000 units (1, 8, 15) PEG 1000-2000 units/m2 (1) 5 (9) LAS: 9 (2-20) PEG: 2   
E2993 Induction LAS 10000 units (17-28) PEG 2500 units/m2 (5, 22) 13 (24) LAS: 15 (2-16) PEG: 1 (1-2)  
Intensification LAS 10000 units (2, 9, 23) PEG 2500 units/m2 (2, 23)  
CCG 1941 Induction PEG 2000 units/m2 (2, 16) 7 (13) 2 (1-4)  
Intensification (5 cycles) PEG 2000 units/m2 (5)  
CALGB 9111 Course I LAS 6000 units/m2 (4, 7, 11, 15, 18, 22) 20 (37) 8 (2-19)  
Course II LAS 6000 units/m2 (15, 18, 22, 25, 43, 46, 50, 53)  
C10403 Induction ± Extension PEG 2500 units/m2 (4) 9 (17) 4 (1-8)  
Consolidation PEG 2500 units/m2 (15, 43)  
Interim Maintenance PEG 2500 units/m2 (2, 22)  
Delayed Intensification PEG 2500 units/m2 (4, 43)  
Regimen Phase or Duration Dose (Cycle days) Patients
n (%) 
Median Doses/Pt  
Augmented Hyper-CVAD (AHC) 8 cycles LAS 20000 units (1, 8, 15) PEG 1000-2000 units/m2 (1) 5 (9) LAS: 9 (2-20) PEG: 2   
E2993 Induction LAS 10000 units (17-28) PEG 2500 units/m2 (5, 22) 13 (24) LAS: 15 (2-16) PEG: 1 (1-2)  
Intensification LAS 10000 units (2, 9, 23) PEG 2500 units/m2 (2, 23)  
CCG 1941 Induction PEG 2000 units/m2 (2, 16) 7 (13) 2 (1-4)  
Intensification (5 cycles) PEG 2000 units/m2 (5)  
CALGB 9111 Course I LAS 6000 units/m2 (4, 7, 11, 15, 18, 22) 20 (37) 8 (2-19)  
Course II LAS 6000 units/m2 (15, 18, 22, 25, 43, 46, 50, 53)  
C10403 Induction ± Extension PEG 2500 units/m2 (4) 9 (17) 4 (1-8)  
Consolidation PEG 2500 units/m2 (15, 43)  
Interim Maintenance PEG 2500 units/m2 (2, 22)  
Delayed Intensification PEG 2500 units/m2 (4, 43)  

. LAS doses were converted to PEG upon specific protocol revision or at discontinuation of LAS availability in 2012. Regimens specified a dose cap with the exception of C10403. A total of 399 LAS and PEG doses resulted in 378 instances of ATC repletion. The reimbursement price of ATC in 2000 was estimated at 1.50/unit U.S. dollars (USD) and 3.04/unit USD by the fourth quarter of 2012. The total estimated average sales price was 2,471,745 USD over the study period. C10403 resulted in the highest median number of PEG doses per patient (n = 5) and a median of 17 ATC doses per dose of PEG. This resulted in C10403 being the most expensive regimen with the median expense for ATC replacement being 118,064 USD (chart 1). This conclusion was also seen after comparing different regimens using the most recent 2012 cost estimates. The overall incidence of TE or HE was 17% and equally distributed between regimens (please see accompanying abstract).

Conclusions

Repletion of ATC in patients receiving asparaginase containing chemotherapy regimens is very expensive and continues to add to costs at many centers, without clear benefit, especially with regards to TE and HE. A prospective, randomized, multicenter clinical trial looking to answer this question is the need of the hour.

Disclosures:

No relevant conflicts of interest to declare.

Author notes

*

Asterisk with author names denotes non-ASH members.