One hundred patients (median age, 17 years; range, 0.3 to 82 years) from institutions within and outside of the United States were consecutively enrolled onto our glucarpidase protocol during a seven-year period (). Completed case report forms were returned for 93 patients. Of the seven remaining patients, detailed summaries and laboratory data were submitted for four patients, and survival outcome was determined for all patients. The initial 35, as well as nine of the subsequent, patients received glucarpidase, leucovorin, and thymidine, and 56 patients received leucovorin and glucarpidase without thymidine.
Baseline Characteristics of 100 Patients Who Received Glucarpidase and Leucovorin With or Without Thymidine
Glucarpidase was administered at a median of 96 hours (range, 22 to 294 hours) after the start of the MTX infusion to patients receiving thymidine and a median of 66 hours (range, 22 to 192 hours) to patients not receiving thymidine. Sixty-five patients received one glucarpidase dose, 28 received two glucarpidase doses 24 hours apart, and seven received three glucarpidase doses every 4 hours. Six of the patients who received a single planned dose also received a delayed (> 24 hours) glucarpidase dose.
Glucarpidase was well tolerated. Transient grade 1 adverse events with possible attribution to glucarpidase in seven patients were flushing (n = 2), a feeling of warmth (n = 2), tingling fingers (n = 1), head pressure (n = 1), numbness and burning sensation around the penis (n = 1), minimal burning of face and extremities (n = 1), shaking (n = 1), neck rash 1 day after glucarpidase (n = 1), and erythema and pruritus of face and legs (n = 1). One additional patient receiving warfarin (Coumadin; Bristol-Myers Squibb, New York, NY) experienced a transient increase in prothrombin time from grade 1 to grade 3. Plasma antibody to glucarpidase could not be detected in 28 evaluable patients.
Median plasma MTX concentration preglucarpidase was 28.2 μmol/L (range, 0.37 to 849 μmol/L) in patients receiving thymidine (n = 39) and 12.3 μmol/L (range, 0.76 to 835 μmol/L) in patients not receiving thymidine (n = 36). Plasma MTX concentration decreased within 15 minutes after the first glucarpidase dose by 98.7% (range, 84% to 99.2%) in patients receiving thymidine and by 98.8% (range, 86.1% to 99.5%) in patients not receiving thymidine (). Subsequent scheduled second and third glucarpidase doses did not result in additional decreases in plasma MTX concentration, and only two of six patients who received a delayed glucarpidase dose experienced a ≥ 50% decrease in MTX concentration. A small rebound in MTX concentration was observed in 30 of 75 evaluable patients (). For the postglucarpidase residual MTX, the median terminal elimination half-life of elimination (n = 16) was more than 72 hours (range, 17.6 to > 72 hours), and the median terminal elimination half-life of DAMPA (n = 23) was 5.5 hours (range, 0.7 to > 72 hours).
Fig 1. Disposition of 100 patients who received glucarpidase, indicating pre-existence or absence of grade 4 toxicity before administration of glucarpidase; appropriate or inappropriate increase in leucovorin (LV) rescue within 3 days after the start of high-dose (more ...)
Fig 2. Plasma methotrexate (MTX) concentration/time profiles for 75 patients who had plasma MTX concentration determined by high-performance liquid chromatography. Lines are point to point, and symbols indicating individual measurements are not included. Glucarpidase (more ...)
Leucovorin and 5-mTHF
In 16 patients studied, the median plasma 5-mTHF and leucovorin concentrations before administration of glucarpidase were 14.1 μM (range, 1.2 to 97 μM) and 354 μM (range, 80.2 to 926.3 μM), respectively. 5-mTHF, an active metabolite of leucovorin, was efficiently hydrolyzed by glucarpidase with a median decrease from baseline of 98.6% (range, 75% to 99.9%) 15 minutes after glucarpidase was administered. Plasma leucovorin concentration, which primarily represents the inactive d-isomer, decreased by a median of 17.7% (range, 0% to 62.4%). Leucovorin was administered for a median of 15 days (range, 4 to 36 days; information missing, n = 26).
Reversible toxicities possibly attributable to thymidine were grade 1 somnolence, tremulousness, and light-headedness (n = 1); grade 2 to 3 confusion for two days (n = 1); and grade 2 to 3 neurocortical toxicity on days 10 and 11 of thymidine (n = 1).
Recovery of Renal Function
Serum creatinine peaked at a median of 4 days (range, 1 to 13 days) after HDMTX administration, and recovery of renal function—defined as serum creatinine within normal limits—occurred at a median of 22 days (range, 5 to 77 days) in 70 patients (no recovery as a result of death, n = 12; additional nephrotoxic chemotherapy before renal recovery, n = 2; recovery by glomerular filtration rate, n = 3; insufficient data, n = 13). The median maximum serum creatinine was 4.0 mg/dL (range, 0.8 to 12.7 mg/dL). Sixty-five patients received diuretics, and 27 patients underwent hemodialysis or hemoperfusion for oliguria, for metabolic reasons, or to decrease plasma MTX before administration of glucarpidase. Of 88 surviving patients, 12 patients received additional HDMTX after recovery of renal function with no reported toxicity.
All patients with osteosarcoma (n = 42) and 18 patients with acute lymphoblastic leukemia or non-Hodgkin's lymphoma received MTX as single agent. Additional cytotoxic chemotherapy was administered to 14 patients (missing information n = 26) within 2 weeks of MTX administration, and in these patients, toxicities could not be solely attributed to MTX.
Four patients had grade 4 neutropenia (absolute neutrophil count ≤ 500/μL) before HDMTX administration. Before administration of glucarpidase, 14 patients experienced grade 4 toxicity, including neutropenia (n = 10), mucositis (n = 7), febrile neutropenia (n = 7), nausea/vomiting (n = 3), thrombocytopenia (n = 2), encephalopathy (n = 1), and pulmonary (n = 1).
After administration of glucarpidase, 34 patients experienced grade 4 toxicity, including neutropenia (n = 29), mucositis (n = 15), febrile neutropenia (n = 12), nausea/vomiting (n = 4), skin (n = 2), pulmonary (n = 1), and seizure (n = 1). Reversible grade 4 elevation in hepatic transaminases (ALT) was observed in 18 patients, and grade 4 increase in bilirubin was observed in nine patients. Hematologic toxicity was not severe in most cases, but 31 patients received filgrastim at some point (no filgrastim, n = 41; missing information, n = 28). In patients with osteosarcoma, there were no statistically significant differences in pretreatment and nadir absolute neutrophil count and the pretreatment and nadir platelet counts between patients receiving and not receiving thymidine (data not shown).
There were 12 patient deaths (median age, 41 years; range, 12 to 79 years), six of which were considered directly related to MTX toxicity. These patients experienced grade 4 myelosuppression (n = 5), grade 3 (n = 1) or grade 4 (n = 3) mucositis, sepsis (n = 5), and toxic epidermal necrolysis (n = 2). Initial leucovorin rescue was inadequate in five patients, and leucovorin was discontinued prematurely despite a plasma MTX concentration of more than 0.1 μmol/L in one patient. All six patients had received thymidine. The other six deaths (median age, 60.5 years; range, 42 to 72 years) were primarily attributable to rapid cancer progression.
Analysis of Characteristics Associated With Outcome
Frequencies of baseline characteristics included in the logistic regression analysis are listed in . Variables with statistically significant association (P < .10) to the development of ≥ grade 4 toxicity using single-factor logistic regression analysis are listed in .
Multiple-Factor Logistic Regression Analysis Model for the Risk of Developing ≥ Grade 4 Toxicity
Using multiple-factor logistic regression, analysis administration of glucarpidase more than 96 hours after start of HDMTX was the only parameter that remained statistically significantly when associated with the development of ≥ grade 4 toxicity (). Inappropriate increase in leucovorin, use of diuretics, and any grade 4 toxicity before glucarpidase predicted perfectly for development of ≥ grade 4 toxicity and could not be included in this analysis.
The disposition of each patient applying the only variable associated with ≥ grade 4 toxicity in the multiple-regression analysis, as well as prior grade 4 toxicity and leucovorin rescue, is shown in . Six of the 12 patient deaths occurred among the 14 patients with grade 4 toxicity before glucarpidase administration, and five of these occurred in patients who received inappropriate leucovorin rescue and administration of glucarpidase after more than 96 hours. In contrast, the incidence of grade 4 toxicity was lower in the 76 patients without grade 4 toxicity before glucarpidase and with appropriate leucovorin rescue. In this group (n = 64), administration of glucarpidase ≤ 96 hours after HDMTX exposure appeared to protect from the development of toxicity; only nine patients (14%) developed ≥ grade 4 toxicity compared with six (55%) of 11 patients who received glucarpidase more than 96 hours after HDMTX exposure.
Fig 3. Maximum decrease and rebound increase in plasma methotrexate (MTX) concentration after administration of glucarpidase (CPDG2) in 30 patients. The median peak rebound increase plasma MTX concentration was 3.3% (range, 0.8% to 13.7%) for 20 patients with (more ...)