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VSHP Elections

Ballots were emailed to pharmacists members recently for the election of President-elect, Secretary, Region President-elects and other offices. Please make sure to vote before the deadline.

If you did not receive your ballot, please email contact@vshp.org

FREE CE for VSHP Members!

Webinar-Tuesday, May 5, 2020 - 7:00pm-8:00 pm

Title: PHARMACIST INVOLVEMENT IN A OB/GYN OBOT CLINIC

Presenter:

Andrew Tarasidis, PharmD

Pharmacy Resident

Carillion Clinic

Learning Objectives:

Discuss how the Opioid Abuse problem began.

Describe drug addiction as it presents in the clinic setting

Discuss how to establish the need for a Pharmacist in a recovery program

Discuss acceptable outcomes and future opportunities for pharmacy

Virginia Society of Health-System Pharmacists is accredited by the Accreditation Council

for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Participants of the session who complete the evaluation and provide accurate NABP e-Profile information will have their credit for 1.0 contact hours (0.10 CEU) submitted to CPE Monitor as early as 14 days after the event and no later than 60 days after the event. Please know that if accurate e-Profile information is not provided within 50 days of the event, credit cannot be claimed after that time. The participant is accountable for verifying the accurate posting of CE credit to their CPE Monitor account within 60 days.

UAN # 0108-0000-20-025-L01-P; 0108-0000-20-025-L01-T

This is a member service of VSHP. There is no charge for members to attend. Dues must be current to receive CE credit.

Non-members will be charged $20.

Members:
To register: https://zoom.us/webinar/register/WN_ZDK6gUYUQyWKxb4igj7k_w

After registering, you will receive a confirmation email containing information about joining the webinar.

VSHP Legislative Highlight Alert

Governor signs VSHP-backed legislation to enhance pharmacy technician education and training

Governor Ralph Northam signed legislation strongly supported by VSHP to enhance education and training requirements for pharmacy technicians. A result of a year-long effort through the Board of Pharmacy and with pharmacy stakeholders, the legislation will require new pharmacy technicians to successfully complete an accredited training program approved by the Board and pass a national certification examination.

The bill also requires that the Board of Pharmacy promulgate various regulations related to the law, and to convene a stakeholder workgroup to issue recommendations on expanding pharmacy technician duties and tasks. VSHP is a named work group stakeholder.

We would like to thank the Virginia Pharmacists Association (VPhA) and the National Healthcareer Association for their partnership and support, as well as the Board of Pharmacy for recognizing the need for standardized education for pharmacy technicians. Minimum standards help ensure patient and medication safety, technician workforce preparation, and recruitment and retention of qualified technicians.

VSHP expresses gratitude to Delegate Keith Hodges (R-Urbanna), Senator Lynwood Lewis (D-Accomac) and all co-patrons for sponsoring the legislation, and to Governor Northam for signing it into law. Details of and a link to the legislation are below. We look forward to working with the Board of Pharmacy on implementation.

HB 1304 (Hodges) and SB 830 (Lewis):

Amend current requirements to be registered as a pharmacy technician to require:

Successful completion of (1) a Board-approved accredited or other legally accepted training program and (2) a national certification examination

Accepted training programs include:
- Accredited training program approved by the Board of Pharmacy, including the Virginia Department of Education's Career & Technical Education programs
- Federal or military program
Accepted national certification examinations include:
- Pharmacy Technician Certification Board (PTCB/CPhT)
- National Healthcareer Association (ExCPT/CPhT)
- Grandfather all current registered pharmacy technicians, and delays accreditation requirement until July 1, 2022 to give training programs time to get up to speed
- Require the Board of Pharmacy to promulgate regulations for people who have passed a national certification examination required by the Board but did not complete a Board-approved pharmacy technician training program, who have successfully completed or were enrolled in a Board-approved pharmacy technician training program, or are currently practicing as a pharmacy technician in another U.S. jurisdiction, when the law and regulations take effect
- Create a "pharmacy technician trainee" registered with the Board of Pharmacy for trainees to gain practical experience under the supervision of a pharmacist, only while the trainee is enrolled in an approved training program
- Require the Board of Pharmacy to convene a work group to report recommendations on adding duties and tasks of registered pharmacy technicians

Thank you to all of our VSHP members for reaching out to your legislators and your feedback on our efforts. We are very excited to be part of advancing technician practice, and look forward to leading new advancements next year!

Our legislative efforts and success depend on the continual active support of VSHP members and advocates like you. Please donate to the VSHP PAC today! http://www.vshp.org/Advocate

If you have any questions, please feel free to reach out to our VSHP Lobbyist, Mark Hickman ( mark@commonwealthstrategy.net), or our VSHP Legislative Chair, Natalie Nguyen ( Natalie.Nguyen@vcuhealth.org).

Thrombolytics in Acute Ischemic Stroke Patients

Amanda Fong, Pharm.D. Candidate 2020 and Gretchen M. Brophy, Pharm.D., BCPS, FCCP, FCCM, FNCS

Virginia Commonwealth University School of Pharmacy

A stroke occurs when blood flow to the brain is halted, and is defined as an abrupt-onset focal neurologic deficit that lasts for 24 hours or more and assumed to be of vascular origin.¹ Without blood flow, the brain is deprived of oxygen and brain cells begin to die within minutes. This can lead to long-term brain damage, disability, or death. An ischemic stroke is a type of stroke caused by blood clots or fatty plaque buildup that occludes blood vessels to the brain. Stroke is the fifth leading cause of death in the United States, killing 142,000 people each year. In 2016, someone in the U.S. had a stroke every 40 seconds and someone died from a stroke about every 4 minutes. Approximately 87% of all primary and secondary strokes that occur each year are ischemic strokes.² Most strokes are preventable with lifestyle changes, consistent physical activity, and aggressive control or prevention of certain medical conditions. These modifiable risk factors are shown in Table 1. Some nonmodifiable risk factors include age, low birth weight, sex, race, and genetic factors. Stroke incidence increases as a person ages and risk doubles each decade after the age of 55. Men have a higher risk of stroke compared to women of the same age; however, women who have a stroke later in life are more likely to die from it than men. Strokes are also more prevalent among African Americans, Asian-Pacific Islanders, and Hispanics, and associated with higher mortality.¹ A stroke can not only dramatically affect a patient's life, but there is also a large economic burden in treating stroke. An estimated cost of 34 billion dollars each year is attributed to stroke, including the cost of health care services, medications, and loss in productivity.²

Table 1. Risk factors for ischemic stroke

Nonmodifiable	Modifiable and well documented	Potentially modifiable and less well documented
Age Race Sex Low birth weight Genetic factors	Smoking Hypertension Diabetes Asymptomatic carotid stenosis Dyslipidemia Atrial fibrillation Sickle cell disease Poor diet Obesity Physical inactivity Other cardiac diseases (CHD, HF, PAD)	Migraine Metabolic syndrome Drug and alcohol abuse Inflammation Infection Elevated Lp(a) Homocysteinemia Sleep-disordered breathing

CHF = congestive heart failure; HF = heart failure; PAD = peripheral artery disease; Lp(a) = lipoprotein(a)

The mainstay of early management of an acute ischemic stroke (AIS) has been treatment with intravenous thrombolytics, particularly alteplase, a tissue plasminogen activator (t-PA). The NINDS trial in 1995 was the first to establish the benefit of t-PA treatment in stroke within three hours of onset.³ Later in 2008, the ECASS III trial demonstrated that administering alteplase between 3 and 4.5 hours after onset of stroke symptoms was efficacious, extending the window for alteplase beyond the conventional 3-hour window to 4.5 hours.⁴ According to the 2018 AHA/ASA Guidelines for Early Management of Patients with Acute Ischemic Stroke, IV alteplase is contraindicated in AIS patients who have an unclear or unwitnessed onset of symptoms and whose baseline state was last known to be more than 3 to 4.5 hours prior, as well as patients who have had a previous ischemic stroke, severe head trauma, or intracranial/spinal surgery within the last 3 months.⁵ Alteplase administration may also be harmful for patients with a history of intracranial hemorrhage and those presenting with symptoms of subarachnoid hemorrhage or infective endocarditis. Alteplase is currently the only thrombolytic approved for AIS; however tenecteplase, a newer recombinant t-PA, may be considered as an alternative for AIS patients with minor neurological impairment and no major intracranial occlusion. This was a new recommendation added to the 2018 AIS Guidelines. Alteplase has FDA indications for acute ischemic stroke, acute myocardial infarction, and acute massive pulmonary embolism, while tenecteplase is only approved for managing acute myocardial infarction. While both drugs have the same mechanism of action, tenecteplase is bioengineered to have a longer half-life and duration of action, more resistance to plasminogen activator inhibitor-1, and more fibrin specific. A comparison of characteristics between tenecteplase and alteplase are shown in Table 2. These potential benefits of using tenecteplase over alteplase have led investigators to conduct trials in order to determine how these two drugs compare in terms of safety and efficacy.

Table 2. Comparison of Tenecteplase vs Alteplase^6-9

	TENECTEPLASE	ALTEPLASE
Administration	IV, single bolus *Incompatible with dextrose solutions-lines containing dextrose must be flushed with saline before and after administration	IV, bolus dose + infusion
Distribution (Vd)	Approximates plasma volume	Approximates plasma volume
Half-life (t_1/2)	Biphasic: initial 20-24 min; terminal 90-130 min	Initial: 5 min; 80% cleared within 10 min; fibrinolytic activity for up to 1 hour after infusion
Excretion	Primarily hepatic metabolism, clearance 99-119 mL/min	Primarily hepatic metabolism, clearance 380-570 mL/min
Contraindications	- Active internal bleeding - Hx of cerebrovascular accident - Intracranial or intraspinal surgery or trauma within 2 months - Intracranial neoplasm, arteriovenous malformation, or aneurysm - Bleeding diathesis - Severe uncontrolled HTN	- Active internal bleeding - Recent intracranial or intraspinal surgery or serious head trauma - Intracranial conditions that may increase risk of bleeding - Bleeding diathesis - Severe uncontrolled HTN

The Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis (ATTEST) and the Norwegian Tenecteplase Stroke Trial (NOR-TEST) were randomized, open-label, blinded endpoint tenecteplase versus alteplase trials published in 2015 and 2017, respectively.^10,11 Both were aimed to assess the safety and efficacy of tenecteplase versus alteplase in AIS patients within 4.5 hours of symptom onset. ATTEST was a phase 2 trial with intentions to use results to design a phase 3 clinical trial. There were 104 patients who received either alteplase 0.9mg/kg (max 90mg) with 10% of the dose as an initial bolus and the remainder over a one-hour infusion, or tenecteplase 0.25mg/kg (max 25mg) as a single bolus.¹⁰ The primary endpoint measured was percentage of penumbra salvaged, defined as baseline CT perfusion-defined penumbra volume minus final infarct volume on follow-up non-contrast CT at 24 to 48 hours post-treatment. Results of this trial did not find a significant difference in the primary endpoint nor in any secondary clinical or imaging outcomes, such as incidence of symptomatic intracerebral hemorrhage. The safety outcomes also did not differ significantly between the two groups. This trial showed that tenecteplase did not differ from alteplase in terms of efficacy nor safety, warranting a larger trial to assess treatment of AIS. The authors suggested that tenecteplase may be favored simply due to its ease in administration, if the two were truly noninferior alternatives. To continue their investigation, the ATTEST-2 phase 3 trial is currently in progress and is estimated to be completed in August 2019.

The NOR-TEST phase 3 trial found that tenecteplase was not superior to alteplase.¹¹ In this trial, 1100 patients received IV tenecteplase 0.4mg/kg (max 40mg) or alteplase 0.9mg/kg (max 90mg) and the primary outcome was excellent functional outcome at 3 months, defined as a score of 0-1 on the modified Rankin Scale. Like the ATTEST trial, NOR-TEST did not find any significant differences between alteplase and tenecteplase in the primary or secondary outcomes, and had similar adverse effects. Results showed similar rates of excellent clinical outcome and intracranial hemorrhage between the two treatment groups. It was previously thought that higher doses of tenecteplase would increase symptomatic intracranial hemorrhage and so 0.25mg/kg doses were often used in phase 2 trials. This study, however, demonstrated that the higher 0.4mg/kg tenecteplase dose was safe and most equivalent to the standard 0.9mg/kg alteplase dose. Further investigation is needed to show noninferiority of tenecteplase to alteplase, as well as how safety and efficacy may differ across different severities of AIS.

Another phase 3 trial, EXTEND-IA TNK, aimed to establish noninferiority was published in 2018.¹² It compared tenecteplase versus alteplase in patients who had large-vessel occlusion and was eligible to undergo thrombectomy. Patients received either tenecteplase 0.25mg/kg (max 25mg) or alteplase 0.9mg/kg (max 90mg) for thrombolysis and the primary outcome was reperfusion of >50% of the involved territory or the absence of retrievable thrombus at initial angiography assessment. Tenecteplase was found to be noninferior to alteplase for the primary outcome and was also favored in the ordinal analysis of the modified Rankin Scale score at 90 days (p = 0.04). There were otherwise no significant differences found in other secondary outcomes, nor symptomatic intracranial hemorrhage and death. Thrombectomy was not performed in patients who reached the primary outcome of reperfusion >50%, with the exception of one patient in the tenecteplase group who had residual thrombus. This trial supports tenecteplase as a noninferior alternative to alteplase in treating AIS patients, and is associated with a better 90-day functional outcome. The higher tenecteplase dose of 0.4mg/kg is currently being studied in the EXTEND-IA TNK Part 2 trial, estimated to be completed in 2021.

Tenecteplase has shown promising results as a thrombolytic for the treatment of acute ischemic stroke. Current data show that tenecteplase is similar in safety to alteplase, while having the advantage of ease of administration. Ongoing trials will be crucial in defining noninferiority or superiority of tenecteplase compared to alteplase as relative efficacy is still undetermined. As of today, IV alteplase (0.9mg/kg with maximum of 90mg, administered over 60 minutes with initial 10% of dose given as a bolus over 1 minute) is recommended for AIS patients presenting in the 3 and 4.5 hour window, along with thrombectomy. While alteplase still remains as the drug of choice, the 2018 AHA/ASA Guidelines for Early Management of Patients with Acute Ischemic Stroke has added tenecteplase, 0.4mg/kg single IV bolus, as a potential alternative for patients with no major intracranial occlusion and minor neurological impairment.⁵ Even though this is the first stepping stone towards future developments, current practices will see little impact from this new recommendation. Alteplase has been the standard of care for many years, and because tenecteplase and alteplase have similar contraindications, there is not yet a definitive reason to use tenecteplase over alteplase. Thrombolytics have long been the cornerstone of AIS treatment and, therefore, a better alternative can have a tremendous impact on patients and healthcare.

References

Fagan SC, Hess DC. Stroke. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com.proxy.library.vcu.edu/content.aspx?bookid=1861&sectionid=132515962. Accessed April 21, 2019.
Stroke Facts. Centers for Disease Control and Prevention. https://www.cdc.gov/stroke/facts.htm. Accessed April 21, 2019.
Tissue Plasminogen Activator for Acute Ischemic Stroke. New England Journal of Medicine. 1995;333(24):1581-1588. doi:10.1056/NEJM199512143332401
Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. New England Journal of Medicine. 2008;359(13):1317-1329. doi:10.1056/NEJMoa0804656
Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2018;49(3):e46-e110.
Alteplase. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed May 27, 2019.
Tenecteplase. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed May 27, 2019.
Activase (alteplase) [package insert]. San Francisco, CA: Genentech, Inc.; 2015.
TNKase (tenecteplase) [package insert]. San Francisco, CA: Genentech, Inc.; 2018.
Huang X, Cheripelli BK, Lloyd SM, et al. Alteplase versus tenecteplase for thrombolysis after ischaemic stroke (ATTEST): a phase 2, randomised, open-label, blinded endpoint study. Lancet Neurology. 2015;14(4):368-76.
Logallo N, Novotny V, Assmus J, et al. Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial. Lancet Neurology. 2017;16(10):781-788.
Campbell BCV, Mitchell PJ, Churilov L, et al. Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke. New England Journal of Medicine. 2018;378(17):1573-1582.

Tumor Lysis Syndrome and Venetoclax Use in Chronic Lymphocytic Leukemia

Melody J. Robbins, PharmD

PGY1 Clinical Pharmacy Resident, Sentara Healthcare

Tumor lysis syndrome (TLS) is a series of metabolic abnormalities resulting from the rapid lysis of malignant cells and the subsequent release of their cellular contents into the bloodstream¹. Monoclonal antibodies, kinase inhibitors, chimeric antigen receptor T cells (CAR-T), proteasome inhibitors, and immunomodulatory agents have all been implicated in TLS². Venetoclax, a BCL-2 inhibitor indicated for chronic lymphocytic leukemia (CLL), has a reported TLS incidence of 3.2-12%^2,3. After detailing more about TLS as a disease state, this article will utilize venetoclax in CLL as an example and examine its role in TLS more closely.

It is difficult to define the overall incidence of TLS because there is much variability among those who develop it and no set standard criteria for diagnosis. The inpatient mortality has been reported to be up to 14-21%^4,5. The most common hematologic malignancies associated with TLS include non-Hodgkin's lymphoma (NHL), Burkitt's lymphoma, acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML)^1,5. Other risk factors include any highly proliferative cancer, bulky disease and large tumor burden, preexisting renal failure, baseline elevated uric acid, and/or rapid acting, effective chemotherapy initiation^1,6. Table 1 displays how patients can be stratified into low, intermediate, and high risk for TLS based on the previously mentioned risk factors.

TLS can be triggered by chemotherapy administration, or it can occur spontaneously with certain baseline risk factors such as highly proliferative cancers or large tumor burden^1,6. After tumor cells are lysed, cellular DNA, phosphate, potassium, and cytokines are released into the bloodstream. The released DNA is metabolized into adenosine and guanosine, which are metabolized into xanthine. Xanthine is oxidized to uric acid by xanthine oxidase, which is excreted by the kidneys. The release of cytokines leads to acute kidney injury as well, resulting in phosphate, potassium, and uric acid accumulation. Precipitations of uric acid, xanthine, and calcium phosphate crystals can also contribute to kidney injury. These effects are the hallmark signs of TLS and can be collectively defined as laboratory or clinical TLS⁶. Laboratory TLS is characteristic of ≥ 2 lab abnormalities within 3 days prior to and up to 7 days after initiation of cytotoxic therapy. Clinical TLS is defined as laboratory TLS plus clinical manifestations such as renal insufficiency, cardiac arrhythmias, seizures, and/or sudden death⁶.

If preventive treatment is desired for a patient, hydration with intravenous (IV) fluids can be initiated to a suggested goal of ≥ 2 milliliters (mL)/kilogram (kg)/hour (hr). Hyperuricemia prevention should be initiated at least 24-48 hours prior to chemotherapy and continued 3-7 days afterwards. Allopurinol is an adequate preventive treatment for hyperuricemia in those who are low or intermediate risk patients, while rasburicase is recommended for high risk patients or if baseline uric acid is > 7.5 mg/deciliter (dL)^1,6,7.

Allopurinol is a xanthine oxidase inhibitor and rasburicase is a recombinant urate-oxidase enzyme. Allopurinol inhibits the conversion of hypoxanthine to xanthine and the conversion of xanthine to uric acid, which is a normal end product in humans. Uric acid has a low solubility and is excreted in urine. Rasburicase further breaks down uric acid into allantoin, which is an end product in other animals. Allantoin has a high solubility in the urine, which makes it easier to eliminate. Therefore, with its mechanism of action, rasburicase actually gets rid of uric acid. Allopurinol could possibly increase the incidence of acute kidney injury because it promotes more xanthine formation, which is not very soluble in the urine. Build-up of xanthine and hypoxanthine can lead to precipitation of these metabolites as crystals, leading to obstructive renal injury. Allopurinol is ineffective at breaking down uric acid that is already elevated in patients because it only inhibits the formation of uric acid. It also takes more time to decrease uric acid compared to rasburicase². Please see Table 2 for greater detail on these two hyperuricemic agents.

Treatment for TLS is based on the same principles as prevention. It involves hydration and hyperuricemic treatment with rasburicase or allopurinol. Rasburicase is a better option for decreased renal function and hyperuricemia > 7.5 mg/dL due to its mechanism as discussed previously. Electrolyte abnormalities such as hyperkalemia and hyperphosphatemia can occur in TLS and should be treated as appropriate. Hyperkalemia treatments include IV calcium for cardiac protection, IV insulin with or without dextrose, inhaled beta-2 agonists, and/or cation exchange resins such as sodium polystyrene sulfate (SPS). For hyperphosphatemia, phosphate binders can be considered but their use has little to no supporting data in TLS. Hemodialysis or continuous renal replacement therapy (CRRT) may need to be initiated in refractory hyperphosphatemia with a calcium phosphorus product of ≥ 70, refractory hyperkalemia, symptomatic hypocalcemia, and/or anuria^1,6,7.

The remainder of this article will focus on venetoclax use in CLL and its association with TLS. This agent works by binding to BCL-2 protein and restoring apoptosis processes in tumor cells that overexpress BCL-2³. The first human study with venetoclax examined its safety profile and maximum tolerated dose in refractory CLL. Subjects were enrolled in several different dose escalation groups to multiple targeted doses ranging from 150 mg to 1,200 mg per day. The groups initially started with 200 mg doses, but the first three subjects developed laboratory TLS and so everyone was switched to a test dosing format. Subjects would start with a test dose of 20 mg or 50 mg. In the absence of TLS, they would be ramped up to designated doses of 150 mg, 200 mg, 300 mg, 400 mg, 600 mg, 800 mg, and 1,200 mg per day. With this revised method of dosing, 18 % (10/56 subjects) developed either laboratory or clinical TLS. Three subjects developed clinical TLS associated with renal failure and dialysis, with the result of one death. This led to a further revision in the protocol to create an expansion cohort with a 5-week dose escalation from 20 mg up to a target dose of just 400 mg. Subjects received strict monitoring and IV hydration, allopurinol, and/or rasburicase depending on their baseline risk for TLS. Thirty-five percent (21/60 subjects) of subjects in this expansion cohort were high risk at baseline and received appropriate prevention therapy. One person developed laboratory TLS, but had no sequelae⁸. Overall, this study indicated overall that TLS was more common with venetoclax when starting at higher doses and when increasing doses too quickly. The 5-week ramp up was ultimately safer as shown in the expansion cohort. Therefore, the recommended dosing for venetoclax in CLL according to manufacturer instructions is as follows: 20 mg daily in Week 1, 50 mg daily in Week 2, 100 mg daily in Week 3, 200 mg daily in Week 4, 400 mg daily in Week 5 and thereafter until unacceptable toxicity or disease progression occurs³.

Although the venetoclax dosing regimen described above is the recommended regimen from the manufacturer for avoidance of TLS, the National Comprehensive Cancer Network® (NCCN) guidelines for chronic lymphocytic leukemia/small lymphocytic lymphoma state that "initiation and accelerated escalation of venetoclax (20-400 mg over 3 weeks) with close inpatient TLS monitoring can be done in the subgroup of patients with high tumor burden and where there is concern for rapid disease progression on or following BTK inhibitor therapy. For accelerated escalation, venetoclax is administered at 20 mg on Week 1/Day 1; 50 mg on Week 1/Day 2-3; 100 mg on Week 1/Day 4-7 (all inpatient), then outpatient unless concern for TLS; 200 mg on Week 2/Day 1-7; and 400 mg on Week 3/Day 1-continuous." However, this dosing regimen was only examined in two small studies (with a combined number of 25 subjects) where the patients received intense monitoring and prophylaxis in the hospital, but TLS still occurred in two patients⁹. Therefore, this accelerated regimen should be utilized with caution, especially in high risk patients.

In conclusion, tumor lysis syndrome is a complication that needs to be considered in patients with baseline risk factors and those receiving high risk chemotherapies, such as venetoclax. Hydration and treatment of electrolyte abnormalities are important mainstays of treatment of TLS. For hyperuricemia, rasburicase is a preferred option for treatment in high risk patients and those who have elevated uric acid at baseline, while allopurinol can be considered in lower risk patients. In those who are high risk receiving venetoclax in CLL, it is better to utilize the 5-week ramp up dosing regimen over an accelerated dosing schedule to avoid the potentially fatal complication of tumor lysis syndrome.

Table 1: Risk Scoring for TLS based on type of cancer (Adapted from Coiffer et al.)¹

Type of Cancer	High Risk	Intermediate Risk	Low Risk
NHL	Burkitt's, lymphoblastic, B-ALL	DLBCL	Indolent NHL
ALL	WBC ≥ 100,000	WBC 50,000-100,000	WBC ≤ 50,000
AML	WBC > 50,000, monoblastic	WBC 10,000-50,000	WBC ≤ 10,000
CLL		WBC 10,000-100,000 Treatment w/fludarabine	WBC ≤ 10,000
Solid tumors and other hematologic malignancies (CML, multiple myeloma)		Rapid proliferation with rapid response to therapy	Remainder of patients
NHL = non-Hodgkin's lymphoma, B-ALL = Burkitt's acute lymphoblastic leukemia, DLBCL = diffuse large B-cell lymphoma, ALL = acute lymphoblastic leukemia, AML = acute myeloid leukemia, CLL = chronic lymphocytic leukemia, CML = chronic myeloid leukemia, WBC = white blood cell count

Table 2: Rasburicase and Allopurinol Drug Information^9-12

	Allopurinol	Rasburicase
MOA:	Xanthine oxidase inhibitor	Recombinant urate-oxidase enzyme
Indications:	Gout, nephrolithiasis prevention, TLS prevention	Hyperuricemia associated with malignancy
Dosing:	100-800 mg daily in 2-3 divided doses Dose reduce with decline in renal function	0.05-0.2 mg/kg daily OR 3-7.5 mg as a single dose infused over 30 minutes
Adverse Events:	Rash (HLA-B*5801 patients avoid)	Edema, headache, anxiety, rash, hypophosphatemia, hypervolemia, nausea, vomiting, abdominal pain, constipation, diarrhea, mucositis, hyperbilirubinemia, increased ALT, IgG antibody development, sepsis, pharyngolaryngeal pain, fever
Contraindications:	Hypersensitivity	Hypersensitivity, glucose-6-phosphate dehydrogenase (G6PD) deficiency, methemoglobinemia
Half-life and Time to Effect:	Half-life is 15 hours Median time to uric acid control is 27 hours	Half-life is 16-23 hours Uric acid levels decrease within 4 hours of initiation

References

Coiffer B, Altman A, Pui CH, et al. Guidelines for the Management of Pediatric and Adult Tumor Lysis Syndrome: An Evidence-Based Review. J Clin Oncol. 2008;26:2767-2778.
Williams SM, Killeen AA. Tumor Lysis Syndrome. Arch Pathol Lab Med. 2019;143:386-393.
Venclexta [package insert]. North Chicago, IL. Abbvie Inc; 2016.
Adeyinka A, Bashir K. Tumor Lysis Syndrome. [Updated 2019 Jun 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK518985/.
Pathak R, Giri S, Aryla MR, et al. Predictors of in-Hospital Mortality in Tumor Lysis Syndrome. Blood. 2014;124(21):4862.
Howard SC, Jones DB, Pui CH. The Tumor Lysis Syndrome. NEJM. 2011;364:1844-1854.
Mirrakhimov AE, Voore P, Khan M, et al. Tumor lysis syndrome: A clinical review. World J Crit Care Med. 2015;4(2):130-138.
Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. NEJM. 2016;374:311-322.
Wierda WB, Byrd JC, Abramson JS, et al. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 4.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020;18(2):185-217.
Zyloprim [package insert]. East Brunswick, NJ. Casper Pharma LLC; 2018.
Elitek [package insert]. Bridgewater, NJ. Sanofi-Aventis US LLC; 2009.
Mirrakhimov AE, Voore P, Khan M, et al. Tumor lysis syndrome: A clinical review. J Crit Care Med. 2015;364:1844-1854.

Members in Spotlight

Congratulations to

Leah Selznick - Virginia Commonwealth University School of Pharmacy, one of the recipients of the 2019-2020 ASHP Student Leadership Award

Please help us highlight members by emailing contact@vshp.org

Did You Know...

If you were unable to attend our live webinars, you can view them at http://vshp.org/Webinars

There are 2 options for viewing-one with one hour of pharmacist or pharmacy technician CE credit ($10 CE processing fee) and one without CE.

Clinical Writing Opportunities for APPE Students

As a new year of APPE rotations begin, writing a clinical article for the VSHP newsletter is a great way for students to get publication experience. As preceptors we can co-author these articles with our students, engage them in the writing process, and enhance their rotation experiences. Topics can be anything related to hospital-system pharmacy. Examples include (but are not limited to): new drug updates, national policy updates for hospital pharmacy, guideline updates, therapeutics reviews, and clinical controversies. Articles are generally 1-3 pages in length, and can include tables and figures. Interested member and students should email Steve Glass, contact@vshp.org for more details.

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