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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 51Asparaginase

, MD.

“Enzymes far exceed man-made catalysts in their reaction specificity, their catalytic efficiency, and their capacity to operate under mild conditions of temperature and hydrogen-ion concentration.”1 As drugs, enzymes also have unique disadvantages. They must be extensively purified to eliminate contaminating toxic materials, such as endotoxins, are often rapidly degraded in the body, have limited distribution because of their size, and are often immunogenic. Despite these problems, L-asparaginase (L-Asp) has become an important chemotherapeutic agent in the treatment of acute lymphoblastic leukemia (ALL) and other lymphoid malignancies.2 It has demonstrated effectiveness in induction, and in subsequent phases of various multiagent chemotherapeutic regimens. Because L-Asp is generally not myelosuppressive and is not cross-resistant with other antineoplastic agents, it is easily added to combination chemotherapy protocols. Extensive use of L-Asp in children does not appear to be associated with the development of late adverse effects. The major limitation to the use of L-Asp is dose-limiting clinical hypersensitivity, which develops in 3 to 78% of patients treated with native forms of the enzyme.3–6 Recent technologic advances have enabled pharmacologic studies of L-Asp, which have demonstrated that a significant proportion of patients exposed to multiple courses of asparaginase therapy develop neutralizing antibodies—frequently without clinical symptomatology. This phenomenon, termed “silent hypersensitivity,” may account for some treatment failures.7–9 Additional pharmacokinetic studies of old and new asparaginases should improve our understanding of treatment failures and allow for the development of more rational dosing schedules in individual patients.

The potential for asparaginase treatment stemmed from the observation of Kidd in 1953, who described an activity in guinea pig sera that caused regression of transplanted lymphomas in mice and rats.10,11 This cytolytic activity was not present in horse or rabbit serum. Other unrelated developments during this period contributed to the discovery by Broome, in 1961, that the antilymphoma activity in guinea pig sera was due to L-Asp.12 These included the observations that certain experimental neoplasms, Walker carcinosarcoma 256 and L5178 leukemia, were found to require asparagine, an amino acid previously considered non-essential, to support growth in tissue culture.13,14 Three years later, Campbell and Mashburn and Mashburn and Wriston showed that L-Asp isolated from Escherichia coli (E. coli) exhibited antitumor activity similar to that found in guinea pig sera.15,16 This finding provided a practical source for the production of large quantities of the enzyme for preclinical and clinical investigations.17–20

Today, L-Asp used in the clinic is available in three preparations: two unmodified or native forms, both purified from bacterial sources, and one form modified from one of the native preparations. The native preparations are derived from E. coli (marketed commercially by Merck & Co. as Elspar), or Erwinia chrysanthemi (Erwinia), (available as Erwinia L-asparaginase from Ogden BioServices Pharmaceutical Repository in the United States) for patients allergic to the E. coli product. The Erwinia product is commercially available in Canada and Europe as Erwinase, marketed by Porton. Both native preparations are approved for use in the therapy of patients in the front line and at relapse. A third preparation, PEG–L-asparaginase (nonproprietary name pegasparaginase), is a chemically modified form of the enzyme in which native E. coli L-Asp has been covalently conjugated to monomethoxypolyethylene glycol (PEG). Pegasparaginase (available commercially from Rhone-Poulenc Rorer as Oncaspar) is approved by the Food and Drug Administration for use in combination chemotherapy for the treatment of patients with ALL who are hypersensitive to native (unmodified) forms of E. coli L-Asp.

Mechanism of Action, Chemistry, and In Vitro Activity

L-Asp catalyzes the hydrolysis of L-Asp to L-aspartic acid and ammonia, resulting in the depletion of serum L-Asp. Plasma asparagine is essentially undetectable throughout the entire period in which asparaginase is present. Leukemic lymphoblasts and certain other tumor cells, which lack or have very low levels of L-Asp synthetase, do not synthesize L-Asp de novo and rely on L-Asp supplied in the serum for survival. Early in the development of L-Asp, it was speculated that the enzyme might selectively kill leukemic cells without affecting normal cells that have the ability to synthesize L-Asp de novo via induction of the enzyme asparagine synthetase. This turned out to be a simplistic paradigm as resistance to the drug emerged, primarily via derepression of the L-Asp synthetase gene in tumor cells.21,22 Preclinical and clinical synergies between asparaginase and cytosine arabinoside have been attributed to lowered activity of asparagine synthetase secondary to increased methylation of cytosine residues in the gene encoding this enzyme.23–25

L-Asp has been isolated and characterized from various microorganisms, including many gram-negative bacteria, mycobacteria, yeasts, and molds, as well as from plants and from the plasma of certain vertebrates.26–28 Not all enzymes have been found to have useful antitumor activity. E. coli produces two L-Asps, EC-1 and EC-2; however, only the EC-2 enzyme has substantial antitumor activity.15 Serratia marcescens and Vibrio succinogenes produce L-Asp with activity against lymphomas,29,30 but resources have never been directed toward the large-scale production of these enzymes to conduct studies in the clinic. Most L-Asps (except for the enzyme found in guinea pig serum) can hydrolyze L-glutamine as well as L-Asp.31 The toxicity and spectrum of activity differences observed with different preparations of the enzyme may be due, in part, to differences in L-glutaminase activity also contained in these preparations, as L-glutamine depletion can potentially enhance the antitumor activity of the enzyme, whereas the hydrolysis of L-glutamine, which produces glutamic acid (monosodium glutamate), may contribute to clinical toxicity, especially neurotoxicity.

The purified E. coli L-Asp molecule has a molecular weight of 138,000 to 141,000 daltons and is composed of four identical subunits with an active site on each subunit, whereas the purified Erwinia enzyme has a molecular weight of 138,000 daltons. Both enzymes have high activity and stability and are readily freed from endotoxin. The enzymes from both E. coli and Erwinia have a low Km for L-Asp and are not inhibited by high concentrations of aspartic acid and ammonia. They differ in isoelectric point and lack antigenic cross-reactivity. The L-glutaminase activity of E. coli and Erwinia L-Asp is minor compared with L-Asp activity with maximal rates of hydrolysis of L-glutamine ranging between 3 and 9% of the activity for L-Asp. The Km for glutamine is 100 times greater than that for asparagine, but high doses of asparaginase will deplete circulating glutamine in animals and patients.31 Guinea pig asparaginase has no glutaminase activity but has never been available in sufficient quantities for clinical trials. The purification26 and properties of the E. coli and Erwinia enzymes have been extensively reviewed and are summarized in Table 51.1.13,14,20,26,32,33

Table 51.1. Properties of Therapeutic Asparaginases.

Table 51.1

Properties of Therapeutic Asparaginases.

Preclinical studies in the late 1950s and early 1960s showed that L-Asp was effective against more than 50 murine tumors, including rat and canine lymphosarcomas, rat fibrosarcoma, Walker’s carcinosarcoma, and Jensen’s sarcoma.32,34 The majority of susceptible tumors were of lymphoid origin. Laboratory studies have demonstrated that lymphoid tumors of the T-cell lineage are more sensitive to asparaginase-induced cytotoxicity than are those of the B-cell lineage; however, this observation has not been formally investigated in clinical trials.14,35

Clinical History

L-Asp was first used clinically in 1966 when an 8-year-old boy with multiply relapsed ALL achieved a short, but definite, clinical response following the administration of partially purified guinea pig L-Asp.36 Subsequently, the E. coli-derived drug was taken into phase I and II trials in children and adults.13,37–48 Response rates of 30 to 65% were achieved in patients with relapsed ALL who were treated with L-Asp as a single agent; however, the duration of remission was very short, averaging about 60 days.42 Response rates were generally higher in children than in adults.

L-Asp has also been shown to improve event-free survival when used during the intensification/consolidation phases of ALL treatment protocols,3,6,49,50–52 particularly for patients with high-risk features at diagnosis including T-cell phenotype53 or slow early response to standard induction chemotherapy.52 It has some efficacy in patients with other hematologic malignancies, such as acute myeloid leukemia and non-Hodgkin’s lymphoma,37,54–57 but indications other than ALL have not been formally investigated. No responses to L-Asp have been reported for patients with nonlymphoid solid tumors. Adults with ALL do not tolerate L-Asp as well as do children, thus limiting enthusiasm for clinical trials in older patients.37,55,58–62

Because of its low myelosuppressive activity and non-cross-resistance with other antitumor agents, L-Asp was incorporated into combination chemotherapy protocols for the treatment of relapsed patients with ALL in the late 1960s and early 1970s.45,55,56,63–66 The reinduction rate for children with relapsed ALL ranges from 30 to 75% with the three-drug combination regimen of vincristine, prednisone, and L-Asp but is dependent on the intensity of front-line therapy.45,63,65 The addition of an anthracycline (daunomycin, doxorubicin) to vincristine, prednisone, and L-Asp improves the reinduction rate to 80 to 95% for these patients.67–69 The highest reinduction rates were achieved when PEG–L-Asp was the therapeutic asparaginase used in the treatment protocol.67

Shortly after studies in patients with relapsed ALL demonstrated its safety and efficacy for these patients, L-Asp, in combination with vincristine, prednisone, with or without an anthracycline, was added to the front-line therapy of patients with ALL in induction. Beginning in the late 1970s, asparaginase intensification was also added to front-line therapy.70 It is now common practice to incorporate L-Asp into ALL induction therapy using a variety of doses and dosing schedules, but formal dose-response studies have not been conducted and the optimum dose delivery and schedule have not been defined. This is attributable in large part to the fact that over 90% of children with newly diagnosed ALL achieve remission following combination chemotherapy with vincristine and prednisone, and because of the overall rarity of the disease, it is inherently difficult to conduct a statistically valid study of the efficacy of additional agents in first-remission induction of ALL.

A single dose-response study performed by the Children’s Cancer Study Group in 1976 showed that children treated with total cumulative doses of more than 6,000 U/m2 in induction had a greater probability of achieving a second remission than did children treated with less than 3,000 U/m2.4,70 In humans, native L-Asp preparations are cleared from the plasma with a half-life (t1/2) of 18 to 24 hours, making it necessary to administer the enzyme every 2 to 5 days to replenish continuous asparagine depletion. In 1979, Nesbit and colleagues showed that L-Asp administered intramuscularly (IM) was as effective as the intravenous (IV) route of administration, with reduced anaphylaxis.6 Currently, the preferred route of administration for L-Asp in children with ALL is intramuscular.

In the past 10 years, two randomized trials designed to evaluate the efficacy of intensified L-Asp therapy in the front-line therapy of childhood ALL have been reported. In 1983, Sallan and colleagues reported the results of a randomized trial in patients newly diagnosed with B-precursor ALL (DFCI 77–01), which demonstrated that patients treated with L-Asp intensification (25,000 IU/m2 per week for 20–30 weeks) in combination with other chemotherapeutic agents significantly improved disease-free and event-free survival as compared with patients treated without L-Asp.70 The results were similar in both high- and low-risk patients with B-precursor disease. The inability to complete the prescribed asparaginase therapy by patients randomized to receive the drug was associated with a higher probability of leukemic relapse. Event-free survival at a median follow-up of 9.3 years was 71 ± 9% for the patients treated with asparaginase compared with 31 ± 11% for those not receiving asparaginase.71 Subsequent nonrandomized trials designed to improve event-free survival in high-risk T- and B-lineage patients confirmed the efficacy of multiagent combination chemotherapy protocols that included intensification with L-Asp.3,72 In 1987, the Pediatric Oncology Group (POG) conducted a randomized trial (POG 8704) designed to evaluate the efficacy of high-dose L-Asp consolidation (25,000 IU a week for 20 weeks) as part of a multiagent chemotherapy regimen in patients newly diagnosed with T-lineage ALL or advanced-stage lymphoblastic lymphoma. In this study as well, patients treated with the L-Asp–containing regimens achieved improved disease-free survival as compared with patients treated without L-Asp.53,73 Intensive asparaginase has also been used in the augmented BFM regimen, improving the outcomes for slow early responders to induction chemotherapy.52 Further incorporation of asparaginase intensification into front- and second-line therapy is likely to occur in the near future.

Asparaginase has also been shown to be effective against meningeal leukemia.13,57,74 The enzyme can be given intrathecally, but this is usually not needed since asparagine is depleted from the cerebrospinal fluid (CSF) by diffusion into the circulation as a result of the concentration gradient between the plasma and CSF.75–77

Toxicity

L-Asp has a distinct toxicity profile, characterized primarily by immune mediated hypersensitivity reactions and adverse events related to the inhibition of protein synthesis. Toxicities occur with similar frequencies with all commercially available asparaginases, with the exception of decreased allergic reactions with PEG–L-Asp. Unlike many chemotherapeutic agents, L-Asp causes little bone marrow depression and usually does not affect the gastrointestinal or oral mucosa or hair follicles.

Normal tissues with high rates of protein synthesis (e.g., liver, pancreas, and coagulation system) are most frequently affected by L-Asp therapy. The majority of patients experience some evidence of chemical hepatotoxicity, made manifest by decreases in serum albumin, fibrinogen, and serum lipoprotein levels and increases in serum liver enzyme levels and bilirubin. Hepatic function usually returns to normal when the drug is cleared or discontinued. Clinical hepatotoxicity is rarely dose limiting. Effects on the coagulation system (hypofibrinogenemia, decreased antithrombin 3, coagulopathy, thromboses), evidenced by imbalances in the formation of clotting factors, are common side effects of L-Asp therapy. Despite the high frequency of chemical abnormalities, bleeding episodes or thromboses are infrequently reported and rarely require discontinuation of therapy. If central nervous system thrombosis or hemorrhage occur, therapy with antithrombin 3 or plasma can be helpful in preventing recurrence during continuation of asparaginase therapy. L-Asp can adversely affect both the endocrine (insulin-secreting) and exocrine (digestive enzyme-secreting) cells of the pancreas. Some patients develop signs and symptoms of diabetes due to decreased synthesis of insulin. Hyperglycemia may be more severe when L-Asp is administered in combination with prednisone, but the risk can be reduced if L-Asp is administered after the prednisone.46,78 Up to 15% of L-Asp–treated patients experience acute pancreatitis that becomes manifest as anorexia, nausea and vomiting, and abdominal pain.79 Approximately 2 to 5% of children experience life-threatening clinical pancreatitis, which prohibits further exposure to the drug. Ten percent develop transient hyperamylasemia with mild abdominal discomfort that spontaneously resolves over a few days, which is not a dose-limiting complication. Nonspecific gastrointestinal toxicity (nausea, vomiting, and anorexia) is common in older children and adults treated with intensified asparaginase therapy. Neurotoxicity (depression, lethargy, fatigue, somnolence, confusion, irritability, agitation, dizziness) occurs in up to 25% of adult patients treated with L-Asp,80 but is less common in children. L-glutamic acid (monosodium glutamate), a product of the L-Asp reaction, has well-established neurotoxicity. Neurotoxicity may also result from a lack of L-Asp or L-glutamine in the brain. Blood ammonia levels can be quite high during treatment with L-Asp (ammonia is a product of the L-Asp reaction). A relationship between high blood ammonia levels and either liver toxicity or cerebral dysfunction (e.g., encephalopathy) has not been established. Azotemia occurs frequently in patients receiving L-Asp; however, they rarely experience renal failure. Patients receiving intensive asparaginase therapy may be at increased risk of developing secondary leukemias induced by topoisomerase-targeted drugs.53,81

Hypersensitivity

Very early in the development of L-Asp, it became apparent that the dose-limiting toxicity of the enzyme was clinical hypersensitivity. The most common clinical manifestation of hypersensitivity is urticaria; however, the spectrum of allergic reactions ranges from localized erythema at the injection site to systemic anaphylaxis with subsequent death. Risk factors for L-Asp hypersensitivity include doses above 6,000 IU/m2 a day,41 IV rather than IM administration,6 repeated courses of treatment,82 and single-agent rather than combination chemotherapy.83 The last observation is probably related to the fact that combination therapy produces immunosuppression, which blunts or obliterates an immune response to asparaginase. Grading of clinical hypersensitivity reactions is not necessarily consistent among treating physicians. A suggested classification system is shown in Table 51.2. Re-exposure to asparaginase is generally possible after a grade I or II reaction after premedication with antihistamines; however, the clearance of the drug is significantly shortened. An alternative asparaginase preparation should be used in patients experiencing grade III or IV reactions.

Table 51.2. Grading of Asparaginase Hypersensitivity Reactions.

Table 51.2

Grading of Asparaginase Hypersensitivity Reactions.

Because the onset of a hypersensitivity reaction often requires discontinuation of treatment, alternative forms of L-Asp that are non-cross-reactive with theE. coli preparation were investigated in the clinic early in the development of this therapy. Wade and colleagues were the first to show that L-Asp isolated from Erwinia chrysanthemi exhibited antitumor activity equivalent to that produced by E. coli.30 Erwinia L-Asp was first used in 1970 as an alternative for the E. coli-derived enzyme in patients who had developed hypersensitivity during treatmen,84 and for many years thereafter Erwinia L-Asp was the only alternative L-Asp product available for continuing L-Asp treatment in these patients. However, Erwinia L-Asp itself also causes hypersensitivity. The incidence of severe allergic reaction to Erwinia L-Asp is about 2% in children who have never been exposed to L-Asp and increases to about 18 to 23% in children with prior allergy to E. coli L-Asp during initial induction therapy.3,85,86 With intensification of asparaginase therapy, rates of allergic reactions to Erwinia parallel those seen with E. coli and increase to as high as 75%. Attempts to intensify asparaginase therapy with repetitive doses of either E. coli or Erwinia-derived asparaginases led to clinical hypersensitivity reactions in 25 to 80% of patients. In POG study 8602 (ALinC 14), investigators attempted to test an L-Asp intensification regimen in children with newly diagnosed ALL.5 L-Asp was given during the first 2 weeks of induction therapy and, after a 3-week break, weekly at a dose of 10,000 IU/m2 for 20 weeks during consolidation. Two percent of patients in induction and 78% of patients during consolidation experienced clinical allergic reactions to E. coli L-Asp. The majority of these patients were switched to Erwinia L-Asp but subsequently (after two or more doses) also became allergic to the Erwinia-derived preparation. Only 11% of the children entered into the study completed 20 of 24 prescribed asparaginase doses. In contrast, regimens using intensified asparaginase without a break in therapy between induction and consolidation have demonstrated clinical hypersensitivity rates of 20 to 35%.6,70,72,73

In the mid-1970s, several groups began chemically modifying L-Asp in various ways in an attempt to identify a form of the enzyme that was less immunogenic while retaining good antitumor activity.87,88 Abuchowski and colleagues had developed a technique for altering the immunogenicity and pharmacokinetics of various proteins by covalently attaching PEG.89–91 In 1979, they showed that a PEG conjugate of E. coli-derived L-Asp caused tumor regression in transplanted mice with less immunogenicity than the unmodified, native E. coli product despite an increased serum t1/287,92 Pegasparaginase was entered into clinical trials in 1984 and has since been administered to more than 1,000 patients with ALL.8,9,93–105 The PEG-conjugated enzyme is less immunogenic than either of the available native products and can be administered safely to most patients with allergic reactions to E. coli or Erwinia L-Asp.9,106,107 Furthermore, the longer serum t1/2 of pegasparaginase allows for a longer interval between doses.9

During a phase I dose-escalation study, 31 adult patients with advanced-stage hematologic malignancies received pegasparaginase by IV infusion over 60 minutes (doses ranging from 500 IU/m2 to 8,000 IU/m2 every 2 weeks.96,97 Major toxicities were hypoalbuminemia and hepatic dysfunction. Three patients developed anaphylactic reactions; two of these had a prior history of hypersensitivity to native L-Asp preparations. There was no clear relationship between the dose of pegasparaginase and toxicity; however, the maximum tolerated dose was not reached in this study. Responses were seen in patients with lymphoma and ALL.

In an early multicenter phase II trial, children or young adults with ALL or acute undifferentiated leukemia in bone marrow relapse received a single dose of pegasparaginase in a 14-day up-front therapeutic window prior to standard multiagent induction chemotherapy.94 The 28-day induction regimen included pegasparaginase 2,000 IU/m2 injected IM once every 2 weeks plus IV vincristine and prednisone beginning on day 14 with or without doxorubicin and intrathecal chemotherapy on day 14. All patients had been heavily pretreated with native L-Asp preparations during previous induction therapies, including nine patients who had developed hypersensitivity reactions. The response rate (CR + PR) was 30% on day 14 when pegasparaginase was used as a single agent and 61% on day 35 following the multiagent induction regimen. Mild (grade 2 or lower by National Cancer Institute Common Toxicity Criteria [CTC]) asp-associated hypersensitivity reactions occurred in one of nine (11%) hypersensitive patients and 5 of 33 (15%) nonhypersensitive patients. The most common nonallergic toxicities were elevated transaminases and coagulation abnormalities. There were no new or unusual L-Asp–related toxicities reported. The results of this study showed that pegasparaginase could be safely administered to patients with and without known hypersensitivity to native L-Asp preparations, and that pegasparaginase was effective when administered every 2 weeks (compared with three times per week for native preparations) during reinduction therapy. PEG-asparaginase also showed activity against cutaneous T-cell malignancies and chronic lymphoblastic leukemia (CLL) in anecdotal patients treated on a concurrent compassionate-use protocol. In the course of clinical development, 33 patients received prolonged therapy with pegasparaginase under maintenance protocols. In the majority of cases, L-Asp was administered intermittently as a single agent at a dose of 2,500 IU/m2 for up to 2 years. No new or unexpected toxicities were observed after prolonged use of the enzyme.

A randomized trial designed to compare the safety, efficacy, and feasibility of administering pegasparaginase versus native E. coli L-Asp as part of a standard induction regimen in children with ALL in second relapse was conducted by POG 8866 from 1988 to 1992.98 All 76 patients enrolled in this study had been previously treated with native L-Asp as part of their front-line therapy. Of the 74 evaluable patients, 35 without prior hypersensitivity to L-Asp were randomized to treatment with either pegasparaginase (2,500 IU/m2 IM every 2 weeks) or native E. coli (10,000 IU/m2 IM three times per week) in combination with a standard 28-day induction regimen of weekly vincristine and daily prednisone. Thirty-nine patients with a history of hypersensitivity were not eligible for randomization and were directly assigned to treatment with pegasparaginase in combination with vincristine and prednisone. The overall CR rate was 40% with no significant differences among the three treatment groups. Two patients, not previously hypersensitive to native asparaginase and randomized to the native E. coli arm, experienced severe (CTC grade 3 or higher) hypersensitivity reactions to native L-Asp, were crossed over to pegasparaginase, and subsequently achieved a complete remission. Interestingly, pharmacokinetic studies of one of these patients demonstrated the phenomenon of “silent hypersensitivity” with subtherapeutic serum asparaginase levels during continued dosing with the native drug during the week prior to his clinical allergic reaction (Fig. 51.1). No unexpected serious adverse reactions were seen in the patients treated with pegasparaginase, and, in general, nonallergic L-Asp–related toxicities were similar among all three treatment groups.

Figure 51.1. Asparaginase pharmacokinetics in ASP-304 patient 1003.

Figure 51.1

Asparaginase pharmacokinetics in ASP-304 patient 1003. Cross-over from E. coli to PEG–L-Asp. Silent hypersensitivity (period during which serum asparaginase levels fell despite continued dosing, indicated by three large arrows) occurred in this (more...)

The lack of new or unusual toxicity in the POG 8866 study and other trials in patients with relapsed ALL led to the evaluation of the biweekly dosing schedule of pegasparaginase in patients newly diagnosed with ALL in front-line pilot studies conducted by the POG, Dana-Farber Cancer Institute, and the Children’s Cancer Study Group between 1992 and 1994. Increased toxicity, specifically related to L-Asp depletion (e.g., pancreatitis, hypoproteinemic syndromes), was observed in this group of L-Asp–naive patients treated with the biweekly dosing schedule. Particularly affected was a subset of patients with high-risk disease on prolonged pegasparaginase therapy in combination with intermediate dose methotrexate, IV 6-mercaptopurine, and IV cytosine arabinoside.100 Despite the increased nonallergic toxicity, fewer hypersensitivity reactions were observed when compared to historic controls who had received native L-Asp preparations as front-line therapy.

As part of a clinical study conducted at Dana-Farber Cancer Institute (Study 8701), Asselin and colleagues prospectively evaluated the in vitro and in vivo efficacy of the three most widely used L-Asp preparations to determine if evidence of an early biologic response could predict long-term outcome.7,108 Children newly diagnosed with ALL were randomized to receive a single dose of E. coli L-Asp, Erwinia L-Asp, or pegasparaginase on day 0 of a 5-day investigational window prior to the initiation of standard induction chemotherapy. The induction remission regimen included two sequential doses of IV doxorubicin, weekly IV vincristine, a single IV dose of methotrexate (MTX) (randomized to high dose or standard dose), daily IV prednisone, and two doses of intrathecal cytosine arabinoside (ara-C). All three types of L-Asp produced equivalent leukemic cell kill in both the in vitro and in vivo assays. These are the first data available demonstrating equivalent efficacy among the three preparations.108 The data also suggested a correlation between in vitro response and the absence of future leukemic relapse. Among the patients classified as nonresponders, 36% had a clinical relapse, whereas none of the patients classified as in vitro responders relapsed. Although the sample sizes were too small to demonstrate a statistically significant relationship, the trend suggested that a lack of early response in vitro to L-Asp as a single agent was predictive of a higher risk of relapse. The incidence of acute toxicity due to L-Asp was low in this study and equivalent among the three preparations.

Asparaginase Pharmacology

Extensive pharmacologic testing has been conducted as part of the clinical evaluation of pegasparaginase. Because the technology for studying the pharmacology of L-Asps was not available when the drug was being developed, this provided an incentive to study the pharmacology of native forms of the enzyme as well.

A pharmacologic assessment of L-Asp was conducted in 27 evaluable patients as part of the phase I study conducted at M.D. Anderson Cancer Center.96,97 The patients in this study were dosed intravenously. The mean serum t1/2 of pegasparaginase was shown to be approximately 15 days. This compared with a mean t1/2 of about 24 hours for the unmodified E. coli preparation and 10 hours for Erwinia L-Asp.97 The rate of total clearance of pegasparaginase was 17-fold lower than that of the unmodified enzyme, whereas the volume of distribution was similar for the two preparations. Preliminary studies showed that L-Asp levels were undetectable immediately following the 1-hour infusion of pegasparaginase and remained low during the 14-day interval between doses.96

Asselin and colleagues described comparative pharmacokinetics of the three L-Asp preparations.93 Single IM doses of 25,000 IU/m2 or E. coli and Erwinia L-Asp were compared with 2,500 IU/m2 of pegasparaginase in children newly diagnosed with ALL treated using an up-front 5-day investigational window of L-Asp therapy. Serum L-Asp levels were monitored for 28 days. The serum half-lives of the three preparations, as well as the duration of L-Asp depletion following administration of the enzyme, are shown in Table 51.3. The data show that the t1/2 of L-Asp is dependent on the enzyme preparation used. The t1/2 of Erwinia L-Asp was significantly shorter (p < .001), whereas the t1/2 of pegasparaginase was significantly longer (p < .001) than that of the standard E. coli L-Asp preparation. The duration of L-Asp depletion following administration of the different L-Asp preparations correlated with the serum t1/2 of the enzyme (i.e., shortest for the Erwinia preparation and longest for pegasparaginase). The L-Asp preparation-dependent pharmacokinetics observed in this study provide important information for establishing an appropriate dosing schedule for L-Asp. The longer t1/2 following administration of pegasparaginase affirms the less frequent dosing schedule for this preparation; however, the shortened t1/2 of the t1/2 of the Erwinia preparation as compared with the E. coli preparation suggests that the accepted dosing schedule for Erwinia L-Asp, which is identical to that for E. coli L-Asp, might not be optimal.

Table 51.3. Serum Half-Life (t1/2) of Three L-Asparaginase Preparations in Children Newly Diagnosed with Acute Lymphoblastic Leukemia.

Table 51.3

Serum Half-Life (t1/2) of Three L-Asparaginase Preparations in Children Newly Diagnosed with Acute Lymphoblastic Leukemia.

Several investigators have shown that patients who develop a hypersensitivity reaction to native L-Asp preparations have a decreased t1/2 for the enzyme.13,55,104,109,110 Asselin and colleagues showed in their study that patients who had a hypersensitivity reaction to L-Asp also demonstrated a decreased t1/2 for pegasparaginase as compared with native patients (1.82 ± 0.26 days verses 5.73 ± 3.24 days, respectively).104 However, native L-Asp was cleared much faster (t1/2 could not be calculated) than pegasparaginase in hypersensitive patients who were dosed with native asparaginase preparations after premedication with antihistamines to ameliorate clinical allergy, suggesting a potential benefit for the polyethyleneglycolated (pegalated) asparaginase.

As part of the POG 8866 study described above, plasma L-Asp levels and anti-L-Asp antibody titers were evaluated in children with ALL in relapse treated with L-Asp.98 The data showed that there was a clear correlation between anti-L-Asp antibody titer and clearance of L-Asp (Table 51.4 and 51.5.93 More than 50% of the nonallergic patients developed anti-L-Asp antibodies during induction, which resulted in increased clearance of both native and pegasparaginase preparations. In this regard, clearance of native asparaginase was so rapid that levels could not be detected in serum 20 minutes after a dose and produced no asparagine depletion, whereas clearance of PEG-modified asparaginase decreased the t1/2 from approximately 6 to 1 to 3 days, still depleting asparagine for 5 to 14 days. Baseline antiasparaginase antibody titers were not predictive of asparaginase clearance, but maximal titer over a 4-week treatment period was predictive. This phenomenon of increased anti-L-Asp antibody formation without clinical evidence of hypersensitivity is called silent hypersensitivity.

Table 51.4. Relationship between Anti-L-Asparaginase Antibody Level and Clearance of Pegasparaginase.

Table 51.4

Relationship between Anti-L-Asparaginase Antibody Level and Clearance of Pegasparaginase.

Table 51.5. Relationship between Anti-L-Asparaginase Antibody Level and L-Asparaginase Level.

Table 51.5

Relationship between Anti-L-Asparaginase Antibody Level and L-Asparaginase Level.

An association between high anti-L-Asp levels and decreased rates of remission induction in leukemic patients has been demonstrated in recent studies.104,111 The data suggest that elevated anti-L-Asp antibody titer in both clinically hypersensitive and nonhypersensitive patients can (by neutralizing L-Asp activity and/or increasing clearance) cause suboptimal L-Asp depletion and diminished efficacy. In open-label, multicenter, clinical and pharmacokinetic trials (Enzon 305/307), pegasparaginase was incorporated into multiagent remission induction regimens for children with ALL.106 Patients in relapse or remission and those newly diagnosed were included in the study. The initial cohort of hypersensitive patients and all nonhypersensitive patients treated on the study were dosed with pegasparaginase 2,500 IU/m2 every other week. Pharmacologic parameters (L-Asp and L-Asp levels and anti-L-Asp antibody titers) were obtained prestudy and on specified days during the treatment period. After analysis of the data from the initial cohort of hypersensitive patients, subsequent hypersensitive patients were treated with weekly doses of pegasparaginase. Hypersensitive patients developed higher levels of anti-L-Asp than either of the other patient groups, and the presence of these antibodies was associated with increased clearance of pegasparaginase.

As shown in Table 51.6, serum L-Asp levels correlated with the duration of L-Asp depletion in these patient subgroups. In native patients, 100% (six of six) had continuous L-Asp depletion for the entire 14-day interval between dosing. This compares with 85% (28 of 33) of previously exposed nonhypersensitive patients. In contrast, only 59% of the hypersensitive patients had L-Asp depletion for 14 days. For previously exposed, nonhypersensitive and hypersensitive subgroups, respectively, 94% (31 of 33) and 88% (22 of 25) of patients were continuously depleted of L-Asp for 7 days. Twelve of 13 hypersensitive patients dosed weekly maintained asparagine depletion for 7 days or longer (see Table 51.6).

Table 51.6. Number of Patients Demonstrating Continuous L-Asparagine Depletion Following Pegasparaginase Therapy.

Table 51.6

Number of Patients Demonstrating Continuous L-Asparagine Depletion Following Pegasparaginase Therapy.

The most common toxicities associated with the use of pegasparaginase in these multiagent chemotherapy regimens were hepatotoxicity and coagulation abnormalities. Hemorrhagic and thrombotic events were not seen. Hypersensitive patients were less likely to experience serious L-Asp–related toxicities than nonhypersensitive or native patients, probably due to a shorter t1/2 for L-Asp and a shorter period of L-Asp depletion. Hypersensitivity reactions were seen in both hypersensitive and nonhypersensitive patients. The majority of patients hypersensitive to the native drug were successfully treated with pegasparaginase without developing a clinical hypersensitivity reaction.

As part of POG study 9310, the safety, efficacy, and pharmacology of L-Asp were compared in patients randomized to pegasparaginase (2500 IU/m2) administered weekly versus every 2 weeks in combination with a standard induction regimen in children with relapsed ALL.67 The induction scheme included prednisone, vincristine, doxorubicin, and L-Asp with triple intrathecal therapy (cytosine arabinoside, methotrexate, hydrocortisone). Response data were available for 128 patients. Of these, the overall CR rate was 87% in patients who received pegasparaginase weekly and 82% in patients who received pegasparaginase once every 2 weeks (p = .02). Response significantly correlated with mean plasma L-Asp levels (p = .01). Hypoalbuminemia (56%) and hypofibrinogenemia (50%) were common nonallergic toxicities. Hypersensitivity (mostly grade 1) occurred in 5% of the patients. The results of this study suggest that pegasparaginase administered weekly may be superior to the enzyme administered once every 2 weeks in relapsed patients and that plasma L-Asp and anti-L-Asp levels correlate with response rate.

Drug Interactions

A series of laboratory and clinical investigations with asparaginase in combination with MTX and ara-C illustrate interactions between these drugs.2 When administered together, inhibition of protein synthesis produced by L-Asp appears to diminish the cytotoxic effect of these antimetabolites. Conversely, the delayed administration of asparaginase following the administration of either of these drugs results in pharmacologic synergy. These schedule and time-dependent effects between a preceding dose of asparaginase and a subsequent dose of MTX appear to be related to an asparaginase effect on MTX polyglutamylation,97 a biochemical effect linked to the cellular retention of MTX and its ultimate cytotoxic effect. Clinical studies have shown that administering L-Asp 9 to 10 days before MTX enhanced the antitumor activity of MTX with reduced gastrointestinal and hematologic toxicity.25,112,113 Schedule-dependent synergy associated with high-dose ara-C and L-Asp has also been observed, suggesting the capacity of asparaginase to improve the therapeutic index for high-dose ara-C in patients with acute myeloid leukemia.114

Conclusions

In summary, L-Asp is an important drug in the treatment of patients with lymphoid malignancies. It does not appear to cause late effects and is not myelosuppressive, rendering it an ideal agent for combination chemotherapy regimens for children with leukemia. Recent technologic advances have enabled detailed pharmacokinetic and pharmacodynamic studies of various asparaginase preparations. Taken together, these data indicate that pharmacokinetic and pharmacodynamic factors have a considerable impact on the efficacy of L-Asp therapy, and that defining the optimum dose and dosing schedule of the different asparaginase preparations that are used in the clinic will require an evaluation of pharmacologic end points, at least in patients who were previously treated with L-Asp. The message from these studies suggests that a pharmacologically guided, individualized approach to L-Asp therapy might achieve the best therapeutic outcome. These types of studies, it is hoped, will become the focus of future asparaginase-based treatment protocols.

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