Hypoalbuminemia in children with acute lymphoblastic leukemia: relation to asparaginase therapy and impact on high dose methotrexate elimination

Abstract

Purpose: High-dose methotrexate (HDMTX) therapy is an important component in treatment regimens for acute lymphoblastic leukemia (ALL). Courses are associated with a risk of renal injury, delayed elimination, and increased systemic toxicity. Recently hypoalbuminemia has been recognized as yet another risk factor.

Methods: To examine the impact of serum albumin we reviewed 325 HDMTX 5 g/m2 courses in a cohort of 51 children treated on the NOPHO ALL 2008 protocol, dividing the courses into four groups with different levels of baseline albumin (A < 25 g/L, B 25-29 g/L, C 30-34 g/L and D ≥ 35 g/L).

Results: Hypoalbuminemia was present in 51% of the courses, mostly in the early phases of chemotherapy while asparaginase therapy is ongoing, and especially if given less than 2 weeks after a dose (78%). Hypoalbuminemia had a significant impact on the end-of-infusion serum MTX, depending on the degree of hypoalbuminemia: MTX > 150 µM was seen in 37%, 32%, 20% and 8% in groups A to D. Serum albumin < 30 g/L was significantly associated with low MTX clearance < 10 L/h/1.73m2 (78% vs. 36%) and high AUC ≥ 1000 µM*h (44% vs. 31%). The frequency of rising creatinine or prolonged elimination was not increased, but the risk of stomatitis was significantly higher (42% vs. 19%).

Conclusion: Low serum albumin is caused by concurrent asparaginase therapy and has a clinically significant impact on MTX disposition. Guidelines for administering HDMTX may need adjustment if serum albumin < 30 g/L, and, if possible, HDMTX courses should not be scheduled soon after asparaginase doses.

Keywords: Asparaginase; Childhood leukemia; Hypoalbuminemia; Methotrexate toxicity/clearance.

Fig. 1

Hypoalbuminemia in sequential HDMTX courses. The occurrence of hypoalbuminemia of different degrees (< 25 g/L, 25–29 g/L, or 30–34 g/L) at the time of HDMTX infusions during NOPHO 2008 chemotherapy for ALL. Upper figure: SR and IR patients (n = 41). The first three courses were given during consolidation therapy, the last five after starting maintenance therapy. PEG-asparaginase doses (ASP) were given i.m. from week 5 to week 33, in most cases at 2-week intervals (black bar). Lower figure: HR patients (n = 10). The first six courses were given as part of nine chemotherapy blocks at 3–4-week intervals, the last three during maintenance therapy. ASP was given week 5 and every 3–4 weeks from week 10 to 33. All time points are as scheduled by protocol; some HDMTX courses were delayed for various clinical reasons

Fig. 2

Relation of hypoalbuminemia to time since the last dose of PEG-asparaginase. Infusions given to all three risk groups of ALL are included (n = 325). Time since last dose has been determined as per protocol schedule; some courses have been delayed by a few days relative to the asparaginase dose

Fig. 3

Hypoalbuminemia in relation to intensity of asparaginase therapy. Comparison of serum albumin levels in 38 children with SR and IR ALL treated with 15 doses of ASP at 2-week intervals (ASP × 15, 20 cases), 5 doses at 2-week intervals followed by 3 doses at 6-week intervals (ASP × 8, 14 cases), and children with demonstrated inactivation of ASP (4 cases). The upper panel shows the first three HDMTX courses given during consolidation therapy, the lower panel the next three courses given after starting maintenance chemotherapy, while ASP therapy is still ongoing

Fig. 4

Pharmacokinetic analysis of serum MTX elimination. Data for HDMTX courses with different levels of baseline serum albumin (< 25 g/L, 25–29 g/L, 30–35 g/L, ≥ 35 g/L) have been compared. Panel A-D: MTX concentrations at and after end of infusion; an outlier treated with glucarpidase because of very high MTX concentrations is present in group C. Panel E–H: Peripheral volumes of distribution, MTX clearance, and AUC have been determined using a three-compartment pharmacokinetic model (MTXPK.org) loaded into NONMEM