Shopping Cart

Acute Lymphoblastic Leukemia — a brief overview

Acute lymphoblastic leukemia (ALL) is a form of leukemia involving precursors of B- and T-cell lymphocytes. Originating in the bone marrow and peripheral blood, ALL can spread to other organs including the spleen, liver, and lymph nodes.¹ The global annual incidence rate of ALL is estimated to be 1.1 to 2.1 per 100,000 person-years.^2,3 ALL is typically a cancer of childhood with approximately 60% to 80% of ALL cases found in children.^1,2 While ALL accounts for approximately 30% of childhood cancers, cases of adult ALL amount to less than 1% of all adult cancers.¹ One major difference between ALL in childhood and adulthood is the 5-year overall survival (OS) rate. The OS of ALL in children approaches 90%, whereas estimates in adults range from 20% to 50%.^2,4 Factors for the lower OS rates in adults are believed to be related to more unfavorable cytogenetics and historically inadequate chemotherapy regimens given to adults.² Because of the striking difference in OS, many of the successful chemotherapy regimens used in children are being tried in adults. A key component of these regimens is asparaginase, an enzyme that hydrolyzes asparagine, a nonessential amino acid necessary for leukemia cell survival.^4,5 The original asparaginase formulation utilized an enzyme isolated from Escherichia coli. Subsequently, several other forms have been developed including asparaginase conjugated with monomethoxypolyethylene glycol and asparaginase from an alternative bacteria, Erwinia chrysanthemi. This activity will focus on the use of asparaginase in adult patients and will consider the perspectives of nurses and pharmacists.

Asparaginase – background

Role in cellular metabolism

The concept of using asparaginase in chemotherapy originated in the 1950s and 1960s when guinea pig serum showed efficacy against cancer in murine studies. Ultimately, asparaginase was identified as the serum component possessing the antilymphoma activity, resulting in cell death.^5,6 Asparaginase acts to catalyze the hydrolysis of the amino acid, asparagine, into aspartic acid and ammonia. Due to the range in substrate specificity, the enzyme also hydrolyzes glutamine to glutamic acid and ammonia.⁵ Research and development eventually led to the first asparaginase drug product derived from E coli (Elspar®) in 1978.⁷ As with other biological products, the use of asparaginase may sometimes be hampered by allergic reactions to the protein. Improvements in manufacturing and purification methods as well as new sources of asparaginase have helped reduce allergic reactions. Furthermore, it has been theorized that a human or humanized enzyme may further alleviate allergic reaction. Since humans express 3 enzymes that hydrolyze asparagine (aspartylglucosaminidase, lysophospholipase, and L‑asparaginase‑like 1), their use has been considered as alternatives to bacterial enzymes; however, biological and technical aspects for each enzyme hinder their potential as ALL treatments.⁵

Effect of Asparaginase in Leukemic Cells, Specifically ALL

The use of asparaginase in ALL was prompted by its selective action against leukemic cells. This selectivity is based on leukemic cells requiring exogenous asparagine for survival.⁵ In nonmalignant cells, L-asparagine synthetase produces the amino acid asparagine via glutamine and aspartic acid substrates.^8,9 Conversely, since leukemic cells in ALL have either low or nonexistent levels of L-asparagine synthetase, these cells must obtain asparagine from serum and other fluids.^4,5 Asparaginase lowers serum asparagine levels by hydrolyzing asparagine to aspartic acid and ammonia, leading to decreased protein synthesis in leukemic cells and eventual leukemic cell death via apoptosis.^4,5

Commercially available asparaginase products

Native E. coli product

The original asparaginase product (Elspar®) was derived from E coli and was approved for use in leukemia in 1978.¹⁰ While the drug retains FDA approval, this product is no longer available after manufacturer discontinuation in 2012.¹¹ The E coli asparaginase product (asparaginase) was administered via IM injection or IV infusion 3 times per week at a dose of 6000 International Units/m² (Table 1).¹⁰ Disuse of the original asparginase product occurred before the manufacturer discontinued the drug due to hypersensitivity reactions and has mostly been replaced by asparaginase modified by the addition of monomethoxypolyethylene glycol.

PEGylated products

Attaching monomethoxypolyethylene glycol to biological products, particularly proteins, is a common method utilized to decrease dosing frequency via an increase in plasma half-life.¹² There are 2 approved asparaginase products with covalently attached monomethoxypolyethylene glycol to the enzyme – pegaspargase and calaspargase pegol – mknl. Both pegaspargase and calaspargase pegol – mknl use the E coli-derived enzyme as the active ingredient with numerous monomethoxypolyethylene glycol molecules covalently attached (69-82 monomethoxypolyethylene glycol molecules for pegaspargase; 31-39 monomethoxypolyethylene glycol molecules for calaspargase pegol – mknl).^4,13–15 Beside the number of monomethoxypolyethylene glycol units attached, the products differ by the chemical linker between monomethoxypolyethylene glycol and asparaginase. Pegaspargase uses a succinimidyl succinate linker while calaspargase pegol – mknl uses a succinimidyl carbonate linker.^4,13–15 The addition of monomethoxypolyethylene glycol to asparaginase increases the half-life of asparaginase, thus allowing for less frequent doses.^4,15 Pegaspargase is administered intravenously or intramuscularly on a dosing schedule of every 14 days (or longer). For patients who are ≤ 21 years old, the recommended dose of pegaspargase is 2500 International Units/m², and for patients who are older than 21 years, the recommended dose is 2000 International Units/m² (Table 1). Intravenous infusions are typically administered over 1 to 2 hours, and intramuscular injections should be in a volume of ≤ 2 mL (multiple injection sites should be used for doses > 2 mL).¹⁴ Calaspargase pegol – mknl is approved for use in patients who are 1 month to 21 years of age and is administered by a 1-hour intravenous infusion (2500 units/m²) at a dosing schedule of no less than every 21 days.¹³

Erwinia chrysanthemi–derived products, including recombinant form

Asparaginase from E chrysanthemi is available in 2 products – the native enzyme produced from E chrysanthemi (Erwinaze™ – asparaginase E chrysanthemi) and a recombinant version [Rylaze™ – asparaginase E chrysanthemi (recombinant)-rywn]. Both the native and recombinant versions are indicated for ALL patients who experience hypersensitivity to E coli-derived asparaginase.^16,17 Since the original E coli-derived product is no longer produced, asparaginase E chrysanthemi and asparaginase E chrysanthemi (recombinant)-rywn are effectively used when patients develop hypersensitivity to pegaspargase or calaspargase pegol – mknl.

Asparaginase E chrysanthemi is administered intramuscularly or intravenously, and dosing is based on which E coli asparaginase product is being replaced. When replacing the native asparaginase in ALL treatment regimens, asparaginase E chrysanthemi is dosed at 25,000 International Units/m² for each scheduled dose of native asparaginase. When replacing pegaspargase or calaspargase pegol – mknl, asparaginase E chrysanthemi is dosed at 25,000 International Units/m² administered 3 times per week for 6 doses for each pegaspargase or calaspargase pegol – mknl dose (Table 1).¹⁶

Variability in the availability of asparaginase E chrysanthemi has been an issue in the past in part due to a myriad of contamination issues.¹⁸ In one instance, the FDA allowed the use of the European version (Erwinase) to be imported to ease supply issues.¹⁹ Partly to address shortages of asparaginase E chrysanthemi, a recombinant version was developed. Asparaginase E chrysanthemi (recombinant)-rywn is biologically produced in Pseudomonas fluorescens bacterium with DNA encoding for the E chrysanthemi enzyme.¹⁷ With the DNA sequence from E chrysanthemi and P fluorescens as the manufacturing cell culture, asparaginase E chrysanthemi (recombinant)-rywn does not exhibit cross-reactivity to asparaginases produced from E coli.²⁰ Asparaginase E chrysanthemi (recombinant)-rywn is administered intramuscularly every 48 hours at a dose of 25 mg/m² when replacing pegaspargase or calaspargase pegol – mknl in chemotherapy regimens for ALL or lymphoblastic leukemia (Table 1).¹⁷

Efficacy of asparaginase in ALL

Key clinical trial data in pediatric and adult ALL

Several years after asparaginase was identified as the component in guinea pig serum that possessed preclinical antilymphoma effects, researchers began to investigate the clinical use of asparaginase, eventually leading to its FDA approval in 1978.^4,5 Initially, asparaginase was studied mostly in children since treatment-limiting side effects were observed in adults with products and protocols of the time.^4,5 Through additional studies that modified treatment parameters, the use of asparaginase in young adults and adults with ALL increased with many studies following pediatric-inspired protocols.

There are typically 4 stages of ALL pediatric chemotherapy regimens: induction, consolidation/central nervous system-directed therapy, reinduction (delayed intensification), and maintenance/continuation^4,6 Asparaginase products are commonly used in the induction, consolidation, and reinduction stages.^4,6,21 With numerous clinical trials of asparaginase products conducted over the years, clinicians can find more detailed information in recent reviews that highlight many of the core studies.^4,6,21

The Dana Farber Cancer Institute (DFCI) 77-01 trial compared the addition of asparaginase to the induction and reinduction (intensification) stages of standard contemporary protocols in children. The researchers found that patients in the asparaginase cohort had a significantly greater disease-free survival compared to the control (72% vs 42%, P = 0.04).^4,6,22

For native Erwinia asparaginase in children (administered in the induction, reinduction, and continuation stages), the Italian, Dutch, Hungarian (IDH)-ALL-91 trial found that the asparaginase cohort had improved 10-year disease-free survival compared to control (87.5% vs 78.7%, P = 0.03) and improved 10-year OS (93.7% vs 88.6%, P = 0.05).^4,23 The ongoing phase 2/3 JZP458-201 study for asparaginase E chrysanthemi (recombinant)-rywn has an open-label, single-arm design that includes pediatric and adult ALL and LBL patients.²⁴ Preliminary results from that study in a cohort of patients 1 to 24 years old were the basis for FDA approval using achievement and maintenance of nadir serum asparaginase activity (≥ 0.1 U/mL) as the primary efficacy measure and updated data have been presented at conference proceedings.^25–27

The Children’s Cancer Group (CCG)-1962 study determined that pegaspargase (3 IM doses) could safely replace native asparaginase (21 IM doses) with similar efficacy and less antibody response.^21,28,29 The DFCI 91-01 and DFCI 05-001 trials found no significant differences between event-free survival (DFCI 91-01) or disease-free survival (DFCI 05-001) between pegaspargase and native asparaginase cohorts in pediatric ALL patients.^21,30,31 And, in comparisons between pegaspargase and calaspargase pegol – mknl in children, 2 studies (COG AALL07P4 and DFCI 11-001) found that calaspargase pegol – mknl treatment resulted in prolonged levels of serum asparaginase activity with similar efficacy results.^21,32–34

The indication for calaspargase pegol – mknl is limited to patients who are 1 month to 21 years of age.¹³ Approval of calaspargase pegol – mknl was based on 2 open-label randomized studies, AALL07P4 and DFCI 11-001, in which attainment and maintenance of nadir serum asparaginase activity levels > 0.1 U/mL was the primary efficacy measure.³⁵

Based on the successes of asparaginase-containing protocols in children, there has been a resurgence in the use of asparaginase products in young adults and adults with ALL via pediatric-inspired protocols.^4,36–38 Egler et al⁶ and Juluri et al⁴ summarize a number of the key trials in young adults and adults. One early study, PETHEMA ALL-96, focused on young adults (15-30 years old) receiving native asparaginase and resulted in 98% complete remission, 61% 6-year event-free survival, and 69% 6-year OS in the full cohort.^4,6,39 The GRAALL 2003 and GRAALL 2005 studies included adult patients up to 60 years old and, using pediatric-inspired protocols with native asparaginase, found complete remission of 93.5% (GRAALL 2003) and 91.5% (GRAALL 2005).^4,6,40,41 There appeared to be some stratification of outcomes based on age whereby more patients older than 45 years experienced treatment-related death and higher death rate in complete remission compared to younger patients (23% vs 5%, P < 0.001; 22% vs 5%, P < 0.001, respectively) in the GRAALL 2003 study.^4,40 Also in the GRAALL 2005 study, patients 55 years and older had a lower 5-year event-free survival rate compared to younger patients (25.8% vs 55.7%, P < 0.001).^4,41

Many of the recent clinical trials of pegaspargase focus on using pediatric-inspired treatment regimens. The CALBG 10403 trial used doses and schedules from the established COG AALL0232 study to treat older adolescents and young adult patients with ALL. Results from the study showed improvements in several outcomes compared to historical control. The median event-free survival in the treatment group was 78.1 months compared to 30 months in the historical control group. The estimated 3-year OS was 73% in the treatment group compared to 58% in the historical control group.⁴² Studies have also demonstrated the utility of pegaspargase in older adults using pediatric-inspired regimens. The MSK 12-266 trial used the Children’s Cancer Group 1882 protocol in ALL patients 18 to 60 years old. Results include complete remission/complete remission with incomplete hematologic recovery in 97% of patients, 3-year event-free survival of 67.8%, and 3-year OS of 76.4%.³⁶

The native and recombinant Erwinia asparaginase formulations both have indications for treating adult ALL patients who develop intolerance to E coli asparaginase formulations, which includes monomethoxypolyethylene glycol-ylated versions.^16,17 There appears, however, to be a dearth of studies on the use of Erwinia asparaginase formulations specifically in the adult population. Two retrospective reviews of adult ALL patients with age ranges of 20 to 58 years (median 32 years)⁴³ and 20 to 72 years (median 39 years)⁴⁴ suggest that asparaginase E chrysanthemi can be tolerated in the older patient population.^43,44 The ongoing phase 2/3 JZP458-201 study design for asparaginase E chrysanthemi (recombinant)-rywn accepts patients of any age and preliminary results have been presented at conference proceedings.^26,27,45

Approved indications

The approved indications for each asparaginase product, while similar, do differ in specific ways. Prescribing, dispensing, and administering a product outside of an approved indication would be considered an off-label use of the product. One commonality among all of the asparaginase products is that they are as part of multi-agent chemotherapy regimens, not as single-agent therapeutics.^{10,13,14,16,17} The original product, asparaginase, has an indication for treating patients with ALL as part of a multi-agent chemotherapeutic regimen for the treatment of patients with ALL.¹⁰ Pegaspargase is indicated as part of a multi-agent chemotherapeutic regimen to treat first-line ALL or to treat ALL patients with hypersensitivity to asparaginase.¹⁴ Both of the E chrysanthemi products have indications limited to patients who have developed hypersensitivity to E coli-derived asparaginases. The asparaginase E chrysanthemi product is approved in cases of ALL in a multi-agent chemotherapeutic regimen.¹⁶ Asparaginase E chrysanthemi (recombinant)-rywn is approved as a component of multi-agent chemotherapy treatment for patients (adult and children 1 month or older) with ALL as well as for patients with lymphoblastic lymphoma.¹⁷

Potential for resistance

A major challenge in oncology is the ability of cancer cells to develop resistance to one or more chemotherapy drugs. Development of asparaginase resistance often leads to more intractable disease and a poorer prognosis.⁴⁶ Resistance to asparaginase has been identified at least as early as 1969 in which leukemic cells isolated from patients treated with asparaginase were found to up-regulate asparagine synthetase, which would ostensibly lead to a supply of asparagine to the cancer cells.⁴⁷ Another mechanism of resistance is based on the production of neutralizing antibodies, which effectively remove the protein from the body. Neutralizing antibodies that lead to decreased therapeutic efficacy typically accompany hypersensitivity reactions (discussed below).^4,48 Patients, however, can also experience silent inactivation of asparaginase whereby loss of therapeutic activity occurs without a hypersensitivity reaction.^4,5,49 With the possibility of silent inactivation, therapeutic drug monitoring that includes measuring asparaginase activity may be warranted.⁵⁰

Novel agents in development

Progress on next-generation asparaginase-type drugs continues. One such drug encapsulates asparaginase in donor-supplied red blood cell (RBCasp).⁵¹ The FDA granted fast track status to RBCasp in 2021.⁵² The NOR-GRASPALL 2016 trial investigated the safety and efficacy of RBCasp in patients ages 1 to 45 years old. Newly published results suggest that RBCasp can maintain target asparaginase activity levels (> 0.1 U/mL) for extended periods to allow for dosing every other week.⁵³ Following a similar drug development progression from asparaginase to pegaspargase, researchers have begun investigating monomethoxypolyethylene glycol-modified asparaginase E chrysanthemi, although published studies are limited to preclinical experiments.⁵⁴

If the hypersensitivity reaction was determined to be grade 3 or grade 4, what alternative asparaginase-containing products could safely be used to continue treatment for adult acute lymphoblastic leukemia?

Toxicity and adverse event management

Frequent treatment-associated adverse events

Adverse events associated with asparaginase can be broadly classified into immunological and nonimmunological. Immunological adverse events include hypersensitivity reactions that can span the gamut from mild low-grade reactions (eg, urticaria) to high-grade reactions (eg, anaphylaxis).^4,5,48 Nonimmunological toxicities include hepatotoxicity, hypertriglyceridemia, pancreatitis, hyperglycemia, hypofibrinogenemia, and thrombus.^4,9 One of the factors affecting asparaginase toxicity appears to be substrate specificity whereby the enzyme can also catalyze the hydrolysis of glutamine in addition to asparagine. Increased toxicity or risk of severe side effects appears to correlate with increased activity toward glutamine and the associated increase in ammonia produced in the hydrolysis reaction.^5,55 Glutaminase activity may be beneficial for the anticancer effect of asparaginases, but contrasting results in the literature leave this issue unresolved.⁴⁸ As described below, some of these adverse events may be attenuated through premedication routines and/or changing to a different asparaginase formulation. The prescribing information for the various asparaginase products, however, do not specify premedication regimens.

Allergic reactions/hypersensitivity

Compared to small molecule drugs, biological products, particularly proteins, are especially prone to inducing allergic reactions and hypersensitivity in patients. Asparaginase is no exception. The propensity to elicit hypersensitivity reactions varies by formulation. Up to 33% of patients who receive native asparaginase may experience allergic reactions while the incidence in pegylated versions can range from 3% to 22%.⁴ Once hypersensitivity reactions to E coli-derived asparaginase occurs, Erwinia asparaginase remains an option as per their indications.^16,17 Hypersensitivity to Erwinia asparaginase can also occur with estimates on incidence rates ranging from 3% to 33%.⁴⁸ For asparaginase products that can be administered IM or IV, administration via the IM route appears to be associated with a higher rate of hypersensitivity reactions.⁵⁶

One of the challenges in dealing with hypersensitivity reactions is that some of the milder symptoms (eg, urticaria, pruritus, fever, chills, diaphoresis) of allergic reactions overlap with infusion site reactions.^49,57 Infusion site reactions, however, are not mediated by antibodies, but are typically observed at first dose.^57,58 In addition, the ammonia generated by the action of asparaginase can also produce transient symptoms that are similar to symptoms of hypersensitivity reactions such as nausea, emesis, headache, and dermatitis.^57,58

Management of hypersensitivity reactions may vary based upon each institutional guidelines. These guidelines will often include a premedication regimen (eg, acetaminophen, H1 and/or H2 antihistamines, and/or corticosteroids); reducing the IV infusion rate; dose reductions; and/or switching to an alternative asparaginase product.^49,58,59 If premedication regimens for hypersensitivity are employed, monitoring of asparaginase activity levels is typically recommended.^49,60,61 The type (ie, hypersensitivity vs infusion reaction) and severity of reaction will advise the particular management strategy with the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE), a common resource for grading adverse events.⁶²

The prescribing information sheets for each product provide guidance on treatment of hypersensitivity reactions, although that guidance may not be sufficiently detailed. For the native E coli asparaginase, “serious allergic reactions” would prompt discontinuation of the drug.¹⁰ With the same manufacturer, the monomethoxypolyethylene glycol-modified E coli asparaginases, pegaspargase, and calaspargase pegol – mknl, have identical recommendations for treating hypersensitivity reactions. First, premedication with acetaminophen plus an H1 receptor antagonist plus an H2 receptor antagonist 30 to 60 minutes prior to infusion is recommended. With grade 1 reactions, infusions should continue at 50% of the original infusion rate. If the patient exhibits grade 2 reactions, the infusion should be paused and hypersensitivity symptoms treated and resolved before restarting the infusion at 50% of the original infusion rate. Grade 3 or 4 reactions would warrant permanent discontinuation of pegaspargase or calaspargase pegol – mknl.^13,14 Prescribing information for asparaginase E chrysanthemi simply states to discontinue the drug and treat hypersensitivity symptoms in the event of a “serious hypersensitivity reaction.”¹⁶ Prescribing information for asparaginase E chrysanthemi (recombinant)-rywn recommends discontinuing in the event of “serious hypersensitivity reactions” but also specifies to treat symptoms for grade 2 reactions and, for grade 3 or 4 reactions, to discontinue asparaginase E chrysanthemi (recombinant)-rywn permanently.¹⁷ Recommendations from clinical experts vary with respect to monitoring of serum asparaginase levels. Van der Sluis et al recommend monitoring of serum asparaginase for grade 1 reactions; for reactions of grade ≥ 2, they recommend switching to another asparaginase formulation without monitoring levels.⁴⁹ In addition, patients on E coli-derived asparaginases (native or monomethoxypolyethylene glycol modified) who experience either hypersensitivity reactions or silent inactivation should be switched to an E chrysanthemi-based asparaginase while maintaining serum asparaginase levels ≥ 0.1 International Units/mL.^49,58

Hepatic and pancreatic adverse events

By some estimates, hepatoxicity in the form of hyperbilirubinemia or transaminitis is the most common adverse event in adult ALL patients treated with asparaginase with rates ranging from 25% to 40% (hyperbilirubinemia) and more than 50% for transaminitis.^50,63 Hepatotoxicity may also present as steatosis or cholestasis.^63,64 While the etiology of asparaginase-induced hepatotoxicity is not completely understood, one mechanism appears to be the inhibition of protein synthesis due to depletion of asparagine and possibly glutamine.⁶⁴ Hyperbilirubinemia from pegaspargase is mostly commonly observed during the induction phase, with the incidence declining or not occurring in subsequent treatment cycles.⁹ Recommendations for preventing hepatotoxicity include avoiding concomitant use of alcohol and hepatotoxic drugs (eg, azoles, acetaminophen) and using lower doses of asparaginase formulations.^50,65 Since hepatotoxicity is almost always reversible and generally does not recur on subsequent doses of asparaginase, treatment generally involves modest pharmacotherapy modifications.^2,50 For CTCAE grade 2 hepatotoxicity (hyperbilirubinemia: bilirubin < 3 mg/dL; transaminitis: alanine or glutamine aminotransferase elevated between 3-5X upper limits of normal), asparaginase can be continued. With CTCAE grade 3 or 4 toxicities, the recommendation is to adjust the dose and schedule of concurrent medications or chemotherapy agents that are metabolized by the liver and to hold asparaginase until toxicity is reduced (CTCAE grade 1 for hyperbilirubinemia, CTCAE grade 2 for transaminitis).^2,65

Clinical researchers have proposed premedication regimens that include levocarnitine with or without vitamin B complex, and case studies with children, young adults, and adults suggest that such a regimen may be effective (although additional studies are warranted).^66,67

Pancreatitis is a relatively common, but serious, adverse event in adults receiving asparaginase as part of pediatric-inspired regimens, with incidence rates ranging from 2% to 22%.^50,63 Patients experiencing clinical, symptomatic pancreatitis may present with vomiting and/or severe abdominal pain, with elevation of amylase or lipase levels of > 3 times upper limit of normal for > 3 days with or without the development of pancreatic pseudocyst.⁶⁵ In cases of clinical, symptomatic pancreatitis, expert panels recommend the permanent discontinuation of asparaginase therapy.^50,65 Development of asparaginase-associated pancreatitis is a contraindication for continuing pegaspargase and other forms of asparaginase since there is an increased risk of recurrence with subsequent doses (up to 63%).^65,90,91 However, in cases of chemical pancreatitis (ie, elevated amylase and lipase levels without clinical symptoms of pancreatitis), asparaginase therapy may be continued.⁵⁰

Venous thromboembolic events

While venous thromboembolism (VTE) events associated with asparaginase treatment are generally considered common adverse events that warrant attention, estimates on their incidence in adults vary substantially (roughly 3%-40%).^2,63,70–73 The risk of VTE with asparaginase treatment appears to increase with increasing age. VTE data from a single medical center had incidences of 3% to 5% for pediatric patients, 34% for all adult patients, and 42% for adults ≥ 30 years old.⁶⁵ The effects of asparaginase on VTE risk appear to be associated with increased levels of procoagulant factors and decreased levels of anticoagulant factors.^50,63,74 The affected coagulation factors include antithrombin, fibrinogen, plasminogen, heparin cofactor II, protein C system, antithrombin III, and anticoagulant proteins C and S.^63,65.74 The risks of VTE have prompted the use of premedication regimens in some instances when treating ALL patients with asparaginase.

While randomly controlled trials on the efficacy of such premedication regimens appear to be lacking,⁷⁵ retrospective and descriptive studies provide some perspective. Grace et al reviewed the impact of implementing a prophylactic anticoagulation regimen in a retrospective study and found decreases in the cumulative incidence of VTE and pulmonary embolus (PE), although the changes were not statistically significant. The pre-implementation VTE rate was 41% vs 28% post-implementation (P = 0.32) and pre-implementation PE rate was 16% vs 8% post-implementation (P = 0.34).⁷⁰ Orvain et al in the GRAALL-2005 trial observed a rate of VTE of 16% prior to antithrombin prophylaxis and a decreased rate to 3% after prophylaxis.⁷² In addition, Chen et al retrospectively reviewed the use of cryoprecipitate with fresh frozen plasma vs cryoprecipitate and antithrombin at two academic medical centers.⁷⁶ The researchers did not find a statistically significant difference between the two prophylactic regimens in incidence of VTE or bleeding (grade ≥ 3). Furthermore, while recognizing absence of data from random controlled trials, the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH) provided a guidance on preventing and managing VTE in adult patients receiving asparaginase. Key takeaways for prevention are: (A) weekly monitoring of antithrombin levels when the decision to monitor is made and infuse antithrombin concentrate when levels dip below 50% to 60%; and (B) use of low molecular weight heparin (LMWH) for prophylaxis during ALL induction phases with asparaginase but withhold LMWH in severe thrombocytopenia (platelet count < 30 × 10⁹/L).⁷⁷

Pharmacist and nursing considerations

Recognition of adverse events associated with asparaginase therapy, and approaches for prophylaxis and toxicity management

Nurses and pharmacists should be vigilant in monitoring for the various adverse events as previously mentioned that are often associated with asparaginase therapy (eg, allergic and hypersensitivity reactions, hepatotoxicity, pancreatitis, VTE, etc). By providing the most direct and frequent patient care, nurses are often the first members of the health care team to identify signs and symptoms of asparaginase toxicity.

Use of universal premedication and therapeutic drug monitoring

Since rigorous testing of universal premedication regimens through random controlled trials are lacking, implementation of such regimens tends to occur on a center-by-center basis. Chemotherapy regimens for ALL are complex and many variables contribute to the decisions on premedication regimens. While guidance documents such as those from the SSC of the ISTH of are helpful,⁷⁷ additional rigorous research on the efficacy of premedication regimens is necessary. More commonly, institutions may develop their own specific recommendations such as those described by Bade et al for the University of Maryland Cancer Center.⁷⁸ Monitoring asparaginase activity levels is the primary mechanism to identify silent inactivation and to manage hypersensitivity.⁴⁹ The percentage of medical centers that routinely measure those levels, however, may not be optimum as indicated by Pike et al’s survey of Canadian oncologists where they found only 39.2% of respondents regularly measure asparaginase activity.⁶¹ Advocating and promoting therapeutic drug monitoring by citing expert recommendations (eg, from van der Sluis et al)⁴⁹ may be useful in raising awareness. Health care cost savings could be a beneficial by-product of universal premedication and therapeutic drug monitoring of asparaginase as described by Cooper et al where they calculated a cost savings of approximately $12,000 per patient.⁷⁹

Increased education for patients/families regarding potential toxicities

Patients with cancer, including those undergoing chemotherapy, are subjected to an inordinate amount and variety of stressors.^80,81 The volume of information regarding chemotherapy may add to such stressors. Nurses and pharmacists, due to their training and frequent patient contact, are in valuable positions for providing education to patients and their families regarding medications used in chemotherapy regimens, including asparaginase. In particular, educating patients and caregivers on signs and symptoms related to common asparaginase toxicities may be helpful in early identification and treatment. Sharing a list of online resources can be a helpful approach so that patients and caregivers can access the material when they are able to process the information. Huynh and Bergeron⁵⁹ provide a list of resources specific for asparaginase such as those from Chemocare.com, Memorial Sloan Kettering Cancer Center, and the University of Pittsburgh Medical Center.^59,82–85

Optimizing collaboration between pharmacists and nurses

Finding time and resources to foster collaboration between nurses and pharmacists may be a challenge, but the benefits could outweigh that hurdle. Open communication channels that are founded on trust and transparency can be crucial for collaborative approaches that improve patient care.⁸⁶ With the challenges associated with treating ALL patients, multidisciplinary efforts are essential. Multidisciplinary approaches involving nurses, pharmacists, and others can show demonstrable benefits in terms of improved patient outcomes (eg, reduction in adverse events) and cost savings.⁸⁷

Formulary decision making

Ideally, the decisions by Pharmacy and Therapeutics (P&T) committees on which drugs to include on Formulary can aid prescribers in making the best, evidence-based drug selection for each patient.^88,89 Although nurses have often been overlooked as members of P&T committees, one suggestion of the Academy of Managed Care Pharmacy Partnership Forum is to have a nursing lead on P&T committees.⁸⁹ Doing so will likely lead to improved communication and collaboration between nursing and pharmacy staff. There are limited choices of asparaginase products for P&T committees to consider. Proactive leadership via P&T and related committees that include nursing representation may be useful in dealing with drug shortages such as occurred with native Erwinia asparaginase as discussed by Marini and colleagues.⁹⁰

Clinical pathway development; adherence to national and institutional evidence-based practice

Clinical care pathways, which are multidisciplinary approaches to patient care, can improve the quality of patient care while also improving patient satisfaction in that care.⁹¹ In addition to the involvement of health care professionals in developing clinical pathways, the patient as stakeholder and participant has been increasing, but implementation is varied and can face hurdles.⁹¹ Flexibility in decision-making in clinical care pathways may be limited by the impetus or need to follow established guidelines and recommendations of national/international professional societies or institutions. The National Comprehensive Cancer Network is one such organization that creates and frequently updates practice guidelines including those for ALL.² Nurses and pharmacists, by keeping up-to-date on guidelines, can help inform patients and other stakeholders in the clinical pathway development.

Summary

Asparaginase has become a valuable component of multi-agent chemotherapy regimens for the treatment of ALL. Asparaginase capitalizes on the low- to nonexistent expression of L-asparagine synthetase of leukemia cells. Without L-asparagine synthetase, leukemic cells require exogenous asparagine for survival. Asparaginase lowers the amount of exogenous asparagine, thus selectively targeting and destroying leukemic cells. Several asparaginase products are currently available including native E coli asparaginase, monomethoxypolyethylene glycol-modified E coli asparaginases, and E chrysanthemi asparaginase (native and recombinant). These products differ with respect to dose, dose frequency, and route of administration. Hypersensitivity reactions to asparaginase products are common, which leads to dose/frequency reduction and/or switching to an alternative product. Besides hypersensitivity reactions, common asparaginase toxicities include hepatotoxicity, hypertriglyceridemia, pancreatitis, hyperglycemia, hypofibrinogenemia, and thrombus. Premedication regimens are often used to help mitigate toxicities including hypersensitivity reactions. Oncology nurses and pharmacists should be able to differentiate between the asparaginase products, and continued collaboration between nurses and pharmacists will aid in the mitigation, identification, and treatment of toxicities associated with asparaginase in ALL.

References

1. Terwilliger T, Abdul-Hay M. Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer J. 2017;7(6):e577. doi:10.1038/BCJ.2017.53
2. Douer D, Gökbuget N, Stock W, Boissel N. Optimizing use of L-asparaginase-based treatment of adults with acute lymphoblastic leukemia. Blood Rev. 2022;53:100908. doi:10.1016/J.BLRE.2021.100908
3. Brown PA, Shah B, Advani A, et al. Acute lymphoblastic leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2021;19(9):1079-1109. doi:10.6004/JNCCN.2021.0042
4. Juluri KR, Siu C, Cassaday RD. Asparaginase in the treatment of acute lymphoblastic leukemia in adults: current evidence and place in therapy. Blood Lymphat Cancer. 2022;12:55-79. doi:10.2147/BLCTT.S342052
5. De Morais SB, De Souza TDACB. Human L‑asparaginase: acquiring knowledge of its activation (Review). Int J Oncol. 2021;58(4):11. doi:10.3892/IJO.2021.5191
6. Egler RA, Ahuja SP, Matloub Y. L-asparaginase in the treatment of patients with acute lymphoblastic leukemia. J Pharmacol Pharmacother. 2016;7(2):62-71. doi:10.4103/0976-500X.184769
7. Food and Drug Administrtions. Drugs@FDA: FDA-Approved Drugs - Elspar. Accessed July 8, 2022. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=101063
8. Chiu M, Taurino G, Bianchi MG, Kilberg MS, Bussolati O. Asparagine synthetase in cancer: beyond acute lymphoblastic leukemia. Front Oncol. 2020;9:1480. doi:10.3389/FONC.2019.01480
9. Daley RJ, Rajeeve S, Kabel CC, et al. Tolerability and toxicity of pegaspargase in adults 40 years and older with acute lymphoblastic leukemia. Leuk Lymphoma. 2021;62(1):176-184. doi:10.1080/10428194.2020.1824068
10. Elspar (asparaginase) [package insert]. Deerfield, IL: Lundbeck; 2013.
11. Palmer E. Lundbeck to stop making cancer drug. FiercePharma. Published September 19, 2012. Accessed June 29, 2022. https://www.fiercepharma.com/m-a/lundbeck-to-stop-making-cancer-drug
12. Yadav D, Dewangan HK. PEGYLATION: an important approach for novel drug delivery system. J Biomater Sci Polym Ed. 2021;32(2):266-280. doi:10.1080/09205063.2020.1825304
13. Asparlas (calaspargase pegol – mknl) [package insert]. Boston, MA: Servier Pharmaceuticals; 2021.
14. Oncaspar (pegaspargase) [package insert]. Boston, MA: Servier Pharmaceuticals; 2021.
15. Heo YA, Syed YY, Keam SJ. Pegaspargase: a review in acute lymphoblastic leukaemia. Drugs. 2019;79(7):767-777. doi:10.1007/S40265-019-01120-1
16. ERWINAZE (asparaginase Erwinia chrysanthemi) [package insert]. Palo Alto, CA: Jazz Pharmaceuticals, Inc; 2019.
17. RYLAZE (asparaginase erwinia chrysanthemi (recombinant)-rywn) [package insert]. Palo Alto, CA: Jazz Pharmaceuticals; 2021
18. Palmer E. FDA warning savages Porton for contamination that led to shortage of Jazz Pharma leukemia drug. Published January 25, 2017. Accessed June 29, 2022. https://www.fiercepharma.com/manufacturing/fda-warning-savages-porton-for-contamination-led-to-shortage-jazz-pharma-leukemia
19. Porton BioPharma. Dear Healthcare Professional Letter. Published May 25, 2021. Accessed June 29, 2022. https://www.fda.gov/media/149614/download
20. Lin T, Hernandez-Illas M, Rey A, et al. A randomized phase I study to evaluate the safety, yolerability, and pharmacokinetics of recombinant erwinia asparaginase (JZP-458) in healthy adult volunteers. Clin Transl Sci. 2021;14(3):870-879. doi:10.1111/CTS.12947
21. Bender C, Maese L, Carter-Febres M, Verma A. Clinical utility of pegaspargase in children, adolescents and young adult patients with acute lymphoblastic leukemia: a review. Blood Lymphat Cancer. 2021;11:25-40. doi:10.2147/BLCTT.S245210
22. Sallan S, Hitchcock-Bryan S, Gelber R, Cassady J, Frei 3rd E, Nathan D. Influence of intensive asparaginase in the treatment of childhood non-T-cell acute lymphoblastic leukemia - PubMed. Cancer Res. 1983;43(11):5601-5607.
23. Pession A, Valsecchi MG, Masera G, et al. Long-term results of a randomized trial on extended use of high dose L-asparaginase for standard risk childhood acute lymphoblastic leukemia. J Clin Oncol. 2005;23(28):7161-7167. doi:10.1200/JCO.2005.11.411
24. Jazz Pharmaceuticals. Jazz Pharmaceuticals announces U.S. FDA Approval of Rylaze^TM (asparaginase erwinia chrysanthemi (recombinant)-rywn) for the treatment of acute lymphoblastic leukemia or lymphoblastic lymphoma. Published June 30, 2021. Accessed July 7, 2022. https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-us-fda-approval-rylazetm
25. Food and Drug Administration. FDA D.I.S.C.O. Burst Edition: FDA approves Rylaze (asparaginase erwinia chrysanthemi (recombinant) - rywn) for treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma in adult and pediatric patients 1 month or older who have developed hypersensitivity to E. coli-derived asparaginase. Published July 12, 2021. Accessed July 7, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approves-rylaze-asparaginase-erwinia-chrysanthemi-recombinant-rywn
26. Maese L, Loh ML, Lin T, et al. Initial results from a phase 2/3 study of recombinant erwinia asparaginase (JZP458) in patients with acute lymphoblastic leukemia (ALL)/Lymphoblastic Lymphoma (LBL) who are allergic/hypersensitive to E coli-derived asparaginases. Blood. 2021;138(Supplement 1):2307. doi:10.1182/BLOOD-2021-147023
27. Maese LD, Loh ML, Choi LMR, et al. Efficacy and safety of intramuscular (IM) recombinant Erwinia asparaginase in acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL): The Children’s Oncology Group (COG) AALL1931 study. J Clin Oncol. 2022;40(16_suppl):7001-7001. doi:10.1200/JCO.2022.40.16_SUPPL.7001
28. Avramis VI, Sencer S, Periclou AP, et al. A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children’s Cancer Group study. Blood. 2002;99(6):1986-1994. doi:10.1182/BLOOD.V99.6.1986
29. Dinndorf PA, Gootenberg J, Cohen MH, Keegan P, Pazdur R. FDA drug approval summary: pegaspargase (oncaspar) for the first-line treatment of children with acute lymphoblastic leukemia (ALL). Oncologist. 2007;12(8):991-998. doi:10.1634/THEONCOLOGIST.12-8-991
30. Silverman LB, Gelber RD, Dalton VK, et al. Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood. 2001;97(5):1211-1218. doi:10.1182/BLOOD.V97.5.1211
31. Place AE, Stevenson KE, Vrooman LM, et al. Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial. Lancet Oncol. 2015;16(16):1677-1690. doi:10.1016/S1470-2045(15)00363-0
32. Schore RJ, Devidas M, Bleyer A, et al. Plasma asparaginase activity and asparagine depletion in acute lymphoblastic leukemia patients treated with pegaspargase on Children’s Oncology Group AALL07P4. Leuk Lymphoma. 2019;60(7):1740-1748. doi:10.1080/10428194.2018.1542146
33. Angiolillo AL, Schore RJ, Devidas M, et al. Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic leukemia: results from Children’s Oncology Group Study AALL07P4. J Clin Oncol. 2014;32(34):3874-3882. doi:10.1200/JCO.2014.55.5763
34. Vrooman LM, Blonquist TM, Stevenson KE, et al. Efficacy and toxicity of pegaspargase and calaspargase pegol in childhood acute lymphoblastic leukemia: results of DFCI 11-001. J Clin Oncol. 2021;39(31):3496-3505. doi:10.1200/JCO.20.03692
35. Li RJ, Jin R, Liu C, et al. FDA Approval Summary: calaspargase pegol-mknl for treatment of acute lymphoblastic leukemia in children and young adults. Clin Cancer Res. 2020;26(2):328-331. doi:10.1158/1078-0432.CCR-19-1255
36. Geyer MB, Ritchie EK, Rao A V., et al. Pediatric-inspired chemotherapy incorporating pegaspargase is safe and results in high rates of minimal residual disease negativity in adults up to age 60 with Philadelphia chromosome-negative acute lymphoblastic leukemia. Haematologica. 2021;106(8):2086-2094. doi:10.3324/HAEMATOL.2020.251686
37. DeAngelo DJ, Stevenson KE, Dahlberg SE, et al. Long-term outcome of a pediatric-inspired regimen used for adults aged 18-50 years with newly diagnosed acute lymphoblastic leukemia. Leukemia. 2015;29(3):526-534. doi:10.1038/LEU.2014.229
38. Siegel SE, Stock W, Johnson RH, et al. Pediatric-inspired treatment regimens for adolescents and young adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: a review. JAMA Oncol. 2018;4(5):725-734. doi:10.1001/JAMAONCOL.2017.5305
39. Ribera JM, Oriol A, Sanz MA, et al. Comparison of the results of the treatment of adolescents and young adults with standard-risk acute lymphoblastic leukemia with the Programa Español de Tratamiento en Hematología pediatric-based protocol ALL-96. J Clin Oncol. 2008;26(11):1843-1849. doi:10.1200/JCO.2007.13.7265
40. Huguet F, Leguay T, Raffoux E, et al. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol. 2009;27(6):911-918. doi:10.1200/JCO.2008.18.6916
41. Huguet F, Chevret S, Leguay T, et al. Intensified therapy of acute lymphoblastic leukemia in adults: report of the randomized GRAALL-2005 Clinical Trial. J Clin Oncol. 2018;36(24):2514-2523. doi:10.1200/JCO.2017.76.8192
42. Stock W, Luger SM, Advani AS, et al. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019;133(14):1548-1559. doi:10.1182/BLOOD-2018-10-881961
43. Bigliardi S, Morselli M, Potenza L, et al. Safety profile of Erwinia asparaginase treatment in adults with newly diagnosed acute lymphoblastic leukemia: a retrospective monocenter study. Leuk Lymphoma. 2015;56(3):770-773. doi:10.3109/10428194.2014.933216
44. Horvat TZ, Pecoraro JJ, Daley RJ, et al. The use of Erwinia asparaginase for adult patients with acute lymphoblastic leukemia after pegaspargase intolerance. Leuk Res. 2016;50:17-20. doi:10.1016/J.LEUKRES.2016.08.014
45. Clinicaltrials.gov. An Open-Label Study of JZP-458 (RC-P) in Patients With Acute Lymphoblastic Leukemia (ALL)/Lymphoblastic Lymphoma (LBL). Published October 30, 2019. Accessed July 7, 2022. https://clinicaltrials.gov/ct2/show/NCT04145531
46. Lee JK, Kang SM, Wang X, et al. HAP1 loss confers l-asparaginase resistance in ALL by downregulating the calpain-1-Bid-caspase-3/12 pathway. Blood. 2019;133(20):2222-2232. doi:10.1182/BLOOD-2018-12-890236
47. Haskell CM, Canellos GP. l-asparaginase resistance in human leukemia--asparagine synthetase. Biochem Pharmacol. 1969;18(10):2578-2580. doi:10.1016/0006-2952(69)90375-X
48. Van Trimpont M, Peeters E, De Visser Y, et al. Novel insights on the use of L-asparaginase as an efficient and safe anti-cancer therapy. Cancers (Basel). 2022;14(4):902. doi:10.3390/CANCERS14040902
49. van der Sluis IM, Vrooman LM, Pieters R, et al. Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation. Haematologica. 2016;101(3):279-285. doi:10.3324/HAEMATOL.2015.137380
50. Burke PW, Hoelzer D, Park JH, Schmiegelow K, Douer D. Managing toxicities with asparaginase-based therapies in adult ALL: summary of an ESMO Open-Cancer Horizons roundtable discussion. ESMO open. 2020;5(5):e000858. doi:10.1136/ESMOOPEN-2020-000858
51. Erytech. Eryaspase. Published 2022. Accessed July 8, 2022. https://erytech.com/pipeline/eryaspase/
52. Sternberg A. FDA grants fast track designation to eryaspase in asparaginase hypersensitive ALL. Published July 30, 2021. Accessed July 6, 2022. https://www.cancernetwork.com/view/fda-grants-fast-track-designation-to-eryaspase-in-asparaginase-hypersensitive-all
53. Lynggaard LS, Vaitkeviciene G, Langenskiöld C, et al. Asparaginase encapsulated in erythrocytes as second-line treatment in hypersensitive patients with acute lymphoblastic leukaemia. Br J Haematol. 2022;197(6):745-754. doi:10.1111/BJH.18152
54. Modi T, Gervais D. Improved pharmacokinetic and pharmacodynamic profile of a novel PEGylated native Erwinia chrysanthemi L-Asparaginase. Invest New Drugs. 2022;40(1):21-29. doi:10.1007/S10637-021-01173-8
55. Beckett A, Gervais D. What makes a good new therapeutic L-asparaginase? World J Microbiol Biotechnol. 2019;35(10):152. doi:10.1007/S11274-019-2731-9
56. Burke MJ, Devidas M, Maloney K, et al. Severe pegaspargase hypersensitivity reaction rates (grade ≥3) with intravenous infusion vs. intramuscular injection: analysis of 54,280 doses administered to 16,534 patients on children’s oncology group (COG) clinical trials. Leuk Lymphoma. 2018;59(7):1624-1633. doi:10.1080/10428194.2017.1397658
57. Asselin B. Immunology of infusion reactions in the treatment of patients with acute lymphoblastic leukemia. Future Oncol. 2016;12(13):1609-1621. doi:10.2217/FON-2016-0005
58. Burke MJ, Zalewska-Szewczyk B. Hypersensitivity reactions to asparaginase therapy in acute lymphoblastic leukemia: immunology and clinical consequences. Future Oncol. 2022;18(10):1285-1299. doi:10.2217/FON-2021-1288
59. Huynh VT, Bergeron S. Asparaginase toxicities: identification and management in patients with acute lymphoblastic leukemia. Clin J Oncol Nurs. 2017;21(5):E248-E259. doi:10.1188/17.CJON.E248-E259
60. Salzer W, Bostrom B, Messinger Y, Perissinotti AJ, Marini B. Asparaginase activity levels and monitoring in patients with acute lymphoblastic leukemia. Leuk Lymphoma. 2018;59(8):1797-1806. doi:10.1080/10428194.2017.1386305
61. Pike M, Kulkarni K, MacDonald T. Asparaginase activity monitoring and management of asparaginase hypersensitivity reactions in Canada. J Oncol Pharm Pract. 2021:10781552211055404. doi:10.1177/10781552211055405
62. National Cancer Institute. Cancer Therapy Evaluation Program. Common terminology criteria for adverse events (CTCAE). Updated April 19, 2021. Accessed July 5, 2022. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm
63. Christ TN, Stock W, Knoebel RW. Incidence of asparaginase-related hepatotoxicity, pancreatitis, and thrombotic events in adults with acute lymphoblastic leukemia treated with a pediatric-inspired regimen. J Oncol Pharm Pract. 2018;24(4):299-308. doi:10.1177/1078155217701291
64. Kamal N, Koh C, Samala N, et al. Asparaginase-induced hepatotoxicity: rapid development of cholestasis and hepatic steatosis. Hepatol Int. 2019;13(5):641-648. doi:10.1007/S12072-019-09971-2
65. Stock W, Douer D, Deangelo DJ, et al. Prevention and management of asparaginase/pegasparaginase-associated toxicities in adults and older adolescents: recommendations of an expert panel. Leuk Lymphoma. 2011;52(12):2237-2253. doi:10.3109/10428194.2011.596963
66. Schulte RR, Madiwale M V., Flower A, et al. Levocarnitine for asparaginase-induced hepatic injury: a multi-institutional case series and review of the literature. Leuk Lymphoma. 2018;59(10):2360-2368. doi:10.1080/10428194.2018.1435873
67. Blackman A, Boutin A, Shimanovsky A, Baker WJ, Forcello N. Levocarnitine and vitamin B complex for the treatment of pegaspargase-induced hepatotoxicity: A case report and review of the literature. J Oncol Pharm Pract. 2018;24(5):393-397. doi:10.1177/1078155217710714
68. Aldoss I, Douer D, Behrendt CE, et al. Toxicity profile of repeated doses of PEG-asparaginase incorporated into a pediatric-type regimen for adult acute lymphoblastic leukemia. Eur J Haematol. 2016;96(4):375-380. doi:10.1111/EJH.12600
69. Oparaji JA, Rose F, Okafor D, et al. Risk factors for asparaginase-associated pancreatitis: a systematic review. J Clin Gastroenterol. 2017;51(10):907-913. doi:10.1097/MCG.0000000000000827
70. Grace RF, DeAngelo DJ, Stevenson KE, et al. The use of prophylactic anticoagulation during induction and consolidation chemotherapy in adults with acute lymphoblastic leukemia. J Thromb Thrombolysis. 2018;45(2):306-314. doi:10.1007/S11239-017-1597-7
71. Kashanian SM, Holtzman NG, Patzke CL, et al. Venous thromboembolism incidence and risk factors in adults with acute lymphoblastic leukemia treated with and without pegylated E. coli asparaginase-containing regimens. Cancer Chemother Pharmacol. 2021;87(6):817-826. doi:10.1007/S00280-021-04252-Y
72. Orvain C, Balsat M, Tavernier E, et al. Thromboembolism prophylaxis in adult patients with acute lymphoblastic leukemia treated in the GRAALL-2005 study. Blood. 2020;136(3):328-338. doi:10.1182/BLOOD.2020004919
73. Grover SP, Hisada YM, Kasthuri RS, Reeves BN, MacKman N. Cancer therapy-associated thrombosis. Arterioscler Thromb Vasc Biol. 2021;41(4):1291-1305. doi:10.1161/ATVBAHA.120.314378
74. Sui J, Zhang Y, Yang L, et al. Successful treatment with rivaroxaban of cerebral venous thrombosis and bone marrow necrosis induced by pegaspargase: A case report and literature review. Medicine (Baltimore). 2017;96(46). doi:10.1097/MD.0000000000008715
75. Rank CU, Lynggaard LS, Als-Nielsen B, et al. Prophylaxis of thromboembolism during therapy with asparaginase in adults with acute lymphoblastic leukaemia. Cochrane Database Syst Rev. 2020;10(10):CD013399. doi:10.1002/14651858.CD013399.PUB2
76. Chen Y, Buhlinger K, Perissinotti AJ, et al. Solving coagulation conundrums: comparing prophylaxis strategies in adult patients receiving PEG-asparaginase. Leuk Lymphoma. June 2022:1-8. doi:10.1080/10428194.2022.2087066
77. Zwicker JI, Wang TF, DeAngelo DJ, et al. The prevention and management of asparaginase-related venous thromboembolism in adults: guidance from the SSC on hemostasis and malignancy of the ISTH. J Thromb Haemost. 2020;18(2):278-284. doi:10.1111/JTH.14671
78. Bade NA, Lu C, Patzke CL, et al. Optimizing pegylated asparaginase use: An institutional guideline for dosing, monitoring, and management. J Oncol Pharm Pract. 2020;26(1):74-92. doi:10.1177/1078155219838316
79. Cooper SL, Young DJ, Bowen CJ, Arwood NM, Poggi SG, Brown PA. Universal premedication and therapeutic drug monitoring for asparaginase-based therapy prevents infusion-associated acute adverse events and drug substitutions. Pediatr Blood Cancer. 2019;66(8):e27797. doi:10.1002/PBC.27797
80. Cancer.net. Managing Stress. Published July 2019. Accessed July 8, 2022. https://www.cancer.net/coping-with-cancer/managing-emotions/managing-stress
81. National Cancer Institute. Psychological Stress and Cancer. Published December 10, 2012. Accessed July 8, 2022. https://www.cancer.gov/about-cancer/coping/feelings/stress-fact-sheet?redirect=true
82. Chemocare.com. Asparaginase - Drug Information. Accessed July 8, 2022. https://chemocare.com/chemotherapy/drug-info/asparaginase.aspx
83. Memorial Sloan Kettering Cancer Center. Pegaspargase: Pediatric Medication. Published 2022. Accessed July 8, 2022. https://www.mskcc.org/cancer-care/patient-education/pegaspargase
84. Memorial Sloan Kettering Cancer Center. Asparaginase (Erwinia): Pediatric Medication. Published 2022. Accessed July 8, 2022. https://www.mskcc.org/cancer-care/patient-education/asparaginase-erwinia
85. UPMC Hillman Cancer Center. Asparaginase (Erwinaze). Published 2022. Accessed July 8, 2022. https://hillman.upmc.com/patients/community-support/education/chemotherapy-drugs/asparaginase
86. Goodwillie B, Renteria C. Nursing-pharmacy collaboration: Find the sweet spot. Fierce Healthcare. Published February 26, 2015. Accessed July 8, 2022. https://www.fiercehealthcare.com/hospitals/nursing-pharmacy-collaboration-how-to-find-sweet-spot
87. Devaux M, Boulin M, Mounier M, et al. Clinical and economic Impact of a multidisciplinary follow-up program in lymphoma patients. Cancers (Basel). 2022;14(10):2532. doi:10.3390/CANCERS14102532
88. Schiff GD, Galanter WL, Duhig J, et al. A prescription for improving drug formulary decision making. PLoS Med. 2012;9(5):1-7. doi:10.1371/journal.pmed.1001220
89. Baker D, Barrington C, Cannon E, et al. AMCP Partnership Forum: principles for sound pharmacy and therapeutics (P&T) committee practices: What’s next? J Manag Care Spec Pharm. 2020;26(1):48-53. doi:10.18553/jmcp.2020.26.1.48
90. Marini BL, Brown J, Benitez L, et al. A single-center multidisciplinary approach to managing the global Erwinia asparaginase shortage. Leuk Lymphoma. 2019;60(12):2854-2868. doi:10.1080/10428194.2019.1608530
91. Wind A, van der Linden C, Hartman E, Siesling S, van Harten W. Patient involvement in clinical pathway development, implementation and evaluation - A scoping review of international literature. Patient Educ Couns. 2022;105(6):1441-1448. doi:10.1016/J.PEC.2021.10.007

Back to Top

« Return to Activity