Journal of Hematology Oncology Pharmacy

JOURNAL OF

HEMATOLOGY ONCOLOGY ™ PHARMACY THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICE

TM

ORIGINAL RESEARCH

Determination of Extended Sterility for Single-Use Vials Using the PhaSeal Closed-System Transfer Device Kristin V. Ho, PharmD; Michael S. Edwards, PharmD, MBA, BCOP; Dominic A. Solimando, Jr, MA, BCOP; Anthony D. Johnson, CPhT REVIEW ARTICLES

Cyanocobalamin/Salcaprozate Sodium: A Novel Way to Treat Vitamin B12 Deficiency and Anemia Lillian Smith, PharmD, MBA, CPh; Juan Mosley, PharmD, CPh, AAHIVP; Megan Ford, PharmDc; Jonathan Courtney, PharmDc Overview of the Recent Developments in Chronic Lymphocytic Leukemia, Part 1 Austin J. Combest, PharmD, BCOP, MBA; Ryan C. Danford, PharmD; Elizabeth R. Andrews, PharmD; Ashley Simmons, PharmD; Paulina McAtee, PharmD; Dirk J. Reitsma, MD FROM THE LITERATURE

Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy With commentaries by Robert J. Ignoffo, PharmD, FASHP, FCSHP

WWW.JHOPONLINE.COM

© 2016 Green Hill Healthcare Communications, LLC

CO-EDITORS-IN-CHIEF Patrick J. Medina, PharmD, BCOP Associate Professor Department of Pharmacy University of Oklahoma College of Pharmacy Oklahoma City, OK

Val R. Adams, PharmD, FCCP, BCOP Associate Professor, Pharmacy Program Director, PGY2 Specialty Residency Hematology/Oncology University of Kentucky College of Pharmacy Lexington, KY

SECTION EDITORS CLINICAL CONTROVERSIES

ORIGINAL RESEARCH

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

REVIEW ARTICLES

Christopher Fausel, PharmD, BCPS, BCOP Clinical Director Oncology Pharmacy Services Indiana University Simon Cancer Center Indianapolis, IN

R. Donald Harvey, PharmD, FCCP, BCPS, BCOP Associate Professor, Hematology/Medical Oncology Department of Hematology/Medical Oncology Director, Phase 1 Unit Winship Cancer Institute Emory University Atlanta, GA Scott Soefje, PharmD, MBA, BCOP Director of Pharmacy University Medical Center Brackenridge Austin, TX

Timothy G. Tyler, PharmD, FCSHP Director of Pharmacy Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA

FROM THE LITERATURE

SYMPTOM MANAGEMENT OVERVIEW

Joseph Bubalo, PharmD, BCPS, BCOP Assistant Professor of Medicine Division of Hematology and Medical Oncology Oncology Clinical Pharmacy Specialist OHSU Hospital and Clinics Portland, OR

Robert J. Ignoffo, PharmD, FASHP, FCSHP Professor of Pharmacy, College of Pharmacy Touro University–California Mare Island, Vallejo, CA

EDITORS-AT-LARGE Sandra Cuellar, PharmD, BCOP Director Oncology Specialty Residency University of Illinois at Chicago Medical Center Chicago, IL Robert Mancini, PharmD, BCOP Oncology Pharmacist PGY2 Oncology Residency Director St. Luke’s Mountain States Tumor Institute Boise, ID Ali McBride, PharmD, MS, BCPS, BCOP Clinical Coordinator Hematology/Oncology The University of Arizona Cancer Center Clinical Assistant Professor College of Pharmacy The University of Arizona Tucson, AZ

Sachin Shah, PharmD, BCOP Associate Professor Texas Tech University Health Sciences Center Dallas, TX Steve Stricker, PharmD, MS, BCOP Associate Director US Medical Affairs Oncology Medical Science Liaison–Blue Grass Region Takeda Oncology Florence, KY John M. Valgus, PharmD, BCOP, CPP Hematology/Oncology Senior Clinical Pharmacy Specialist University of North Carolina Hospitals and Clinics Chapel Hill, NC Daisy Yang, PharmD, BCOP Clinical Pharmacy Specialist The University of Texas M. D. Anderson Cancer Center Houston, TX

PUBLISHING STAFF Senior Vice President/Group Publisher Russell Hennessy rhennessy@the-lynx-group.com Publisher Cristopher Pires cpires@the-lynx-group.com Editorial Director Frederique H. Evans fevans@the-lynx-group.com Copyeditor Hina Khaliq Editorial Assistant Katharine Brzozowski Production Manager Wayne Williams THE LYNX GROUP President/CEO Brian Tyburski Vice President, Finance Andrea Kelly Senior Financial Assistant Audrey LaBolle Director, Human Resources Jennine Leale Medical Director Julie Strain Director, Strategy & Program Development John Welz Editorial Director Susan Berry Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Design Managers Chris Alpino Lora LaRocca Director, Digital Marketing Samantha Weissman Digital Content Manager Anthony Trevean Digital Editor John Parkinson Digital Media Specialist Charles Easton IV Jr Digital Content Manager Walford Guillaume Junior Digital Developer Christina Bethencourt Sales Operations Manager Margaret Hoffmann Office Manager/Executive Administrative Assistant Carolyn Jablonski Administrative Assistants Sara Mohamed Colette Puhalski IT Manager Kashif Javaid Office Coordinator Robert Sorensen STRATEGIX President Abigail Adair Account Group Supervisor Karie Gubbins Account Supervisor Deanna Martinez Senior Account Executives George Fuller Meg Spencer Business Development Advisor Saher Almaita ASSOCIATION & CONGRESS DIVISION Association Director Patrice Melluso Meeting & Event Planner Linda Mezzacappa Project Manager Jeremy Shannon Senior Project Coordinator Gretchen Dann Project Coordinator Rachael Baranoski

JOURNAL OF

HEMATOLOGY ONCOLOGY PHARMACY™ THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICE

TM

TABLE OF CONTENTS REVIEW ARTICLES 42 Cyanocobalamin/Salcaprozate Sodium: A Novel Way to Treat Vitamin B12

Deficiency and Anemia

Lillian Smith, PharmD, MBA, CPh; Juan Mosley, PharmD, CPh, AAHIVP; Megan Ford, PharmD(c); Jonathan Courtney, PharmD(c)

54 Overview of the Recent Developments in Chronic Lymphocytic

Leukemia, Part 1 Austin J. Combest, PharmD, BCOP, MBA; Ryan C. Danford, PharmD; Elizabeth R. Andrews, PharmD; Ashley Simmons, PharmD; Paulina McAtee, PharmD; Dirk J. Reitsma, MDa

ORIGINAL RESEARCH 46 Determination of Extended Sterility for Single-Use Vials Using the PhaSeal

Closed-System Transfer Device K ristin V. Ho, PharmD; Michael S. Edwards, PharmD, MBA, BCOP; Dominic A. Solimando, Jr, MA, BCOP; Anthony D. Johnson, CPhT DEPARTMENT

From the Literature 69 Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy

With commentaries by Robert J. Ignoffo, PharmD, FASHP, FCSHP MISSION STATEMENT The Journal of Hematology Oncology Pharm­acy is an independent, peer-reviewed journal founded in 2011 to provide hematology and oncology pharmacy practitioners and other healthcare professionals with high-quality peer-reviewed information relevant to hematologic and oncologic conditions to help them optimize drug therapy for patients.

Journal of Hematology Oncology Pharmacy™, ISSN 2164-1153 (print); ISSN 2164-1161 (online), is published 4 times a year

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REVIEW ARTICLE

Cyanocobalamin/Salcaprozate Sodium: A Novel Way to Treat Vitamin B12 Deficiency and Anemia Lillian Smith, PharmD, MBA, CPh; Juan Mosley, PharmD, CPh, AAHIVP; Megan Ford, PharmDc; Jonathan Courtney, PharmDc

J Hematol Oncol Pharm.

2016;6(2):42-45 www.JHOPonline.com Disclosures are at end of text

Background: Vitamin B12 deficiency anemia is a medical condition characterized by a low red blood cell count and vitamin B12. Various treatment options are available for vitamin B12 deficiency.

Cyanocobalamin comes in an array of formulations, including injection, nasal spray, powder, solution, sublingual, and tablets. However, many oral formulations are considered supplements, which are not regulated by the US Food and Drug Administration.

Objective: The purpose of this review is to compare cyanocobalamin/salcaprozate sodium (SNAC) with other available cyanocobalamin formulations based on pharmacokinetics and efficacy.

Discussion: Injections of vitamin B12 typically have been the predominant method for treating patients who require a fast or highly bioavailable response. However, the pharmacokinetic profile of cyanocobalamin/SNAC was shown to be more favorable than that of another oral formulation of cyanocobalamin (not containing SNAC), because it reached a higher peak plasma concentration than the other oral formulation.

Conclusion: Cyanocobalamin/SNAC is a major advancement in the treatment of hypocobalaminemia because it is the first formulation to include the absorption promoter SNAC. Cyanocobalamin/ SNAC was shown to be as effective as intramuscular cyanocobalamin in restoring normal levels of serum cobalamin, which makes this drug an attractive option for the treatment of patients with vitamin B12 deficiency.

L

ack of sufficient vitamin B12 intake is often associated with the development of vitamin B12 deficiency anemia, which is a medical condition characterized by a low red blood cell count and vitamin B12.

Vitamin B12 deficiency anemia has several causes, including pernicious anemia (PA), which results from autoantibodies destroying the cells that make intrinsic factor. Without intrinsic factor, the body is unable to absorb vitamin B12 through the stomach.

Historically, PA was thought to affect the Scandinavian and Celtic-origin populations more than other ethnic groups; however, more recent evidence has shown higher prevalence in the African and Latin American populations.1,2 Understanding the epidemiology of PA is important when discussing patient populations in clinical trials of medications for correcting abnormal vitamin B12 levels. Data indicate that women are almost twice as likely to be affected as men.1 The median age-group is 40 to 70 years.1-3 Before treatment can be Dr Smith is an Assistant Professor of Pharmacy Practice; Dr Mosley is an Assistant Professor of Pharmacy Practice; Ms Ford is a PharmD candidate; and Mr Courtney is a PharmD candidate, Florida Agricultural and Mechanical University, Tallahassee.

pursued, the appropriate form of subclinical or clinical vitamin B12 deficiency must be diagnosed.

The early diagnosis of vitamin B12 deficiency is important for preventing anemia, but is challenging because patients may be asymptomatic or have only mild symptoms, such as bowel changes, fatigue, loss of appetite, pale skin, shortness of breath, mild tingling of the extremities, and bleeding gums. These mild symptoms, or lack thereof, are associated with the subclinical form of vitamin B12 deficiency, which is also the most common type of vitamin B12 deficiency. The key diagnostic factor for subclinical vitamin B12 deficiency is a cobalamin level between 200 pg/mL and 350 pg/mL.4 The other type of vitamin B12 deficiency is the clinical form, which manifests as anemia or more serious signs and symptoms (eg, depression, confusion, dementia, and paresthesia in the hands and feet). In this type of vitamin B12 deficiency, the cobalamin level is <200 pg/mL.4-6 Correcting vitamin B12 levels is especially important in clinically deficient patients, because nerve damage can be permanent if treatment is not initiated within 6 months of symptom onset.7 Once the diagnosis is confirmed, the healthcare provider must choose a patient-specific vitamin B12 formulation.

Currently there are myriad formulations of which

A Novel Way to Treat Vitamin B12 Deficiency and Anemia

treatment of vitamin B12 deficiency can consist. The purpose of this review is to compare cyanocobalamin/ salcaprozate sodium (SNAC) with other available vitamin B12 formulations based on their pharmacokinetics, efficacy, and cost.

Formulations Cyanocobalamin is the most common commercially available form of vitamin B12. It comes in an array of formulations, including intramuscular (IM) injection, nasal spray, powder, solution, sublingual, and tablet form. Although various treatment options exist, many oral formulations are considered dietary supplements, which are not regulated by the US Food and Drug Administration (FDA), and little clinical data exist to support their use. The current FDA-approved formulations of cyanocobalamin are IM injection, subcutaneous (SC) injection, intravenous (IV) infusion, and nasal spray. IV infusion is not frequently used because cyanocobalamin is lost more rapidly via the urine than with the other parenteral formulations, leaving little time for liver storage and use, and causing less of a therapeutic response.8 Cyanocobalamin is converted to methylcobalamin in vivo by removal of a cyanide group and subsequent methylation. As a result, supplemental methylcobalamin is often presumed to have improved bioavailability and clinical efficacy compared with cyanocobalamin; however, there is insufficient evidence to indicate its superiority.9 Methylcobalamin is available only as a dietary supplement, while cyanocobalamin is available as dietary supplements, FDA-approved medications, and now as a medical food. Also, cyanocobalamin is more stable and less expensive to produce.9 Cyanocobalamin/salcaprozate sodium (Eligen B12; Emisphere Technologies, Roseland, NJ), the newest tablet formulation, differs from other medications and supplements for vitamin B12 deficiency because it contains an oral absorption promoter, known as salcaprozate sodium (SNAC). SNAC chaperones vitamin B12 through the gastric lining into the bloodstream. This added constituent gives cyanocobalamin/SNAC a drug-absorption profile similar to that of injectable vitamin B12, as was shown in a small clinical trial.10 As a result, cyanocobalamin/SNAC has been classified as a medical food.

Medical foods are intended for the nutritional support of patients with a specific disease or condition. Because they are classified as food, they are not subject to drug regulations. For example, medical foods do not have to undergo premarket review or approval, making them similar to dietary supplements. However, unlike supplements, medical foods must comply with all applicable FDA requirements for food, such as regulations of the

Current Good Manufacturing Practice and the Registration of Food Facilities. In addition, medical foods can be labeled for medical conditions, as long as the label is not misleading and based on clinical data. A prescription may also be required for their use. All ingredients contained in medical foods must be generally recognized as safe or approved food additives.11,12 Therefore, it is more difficult to produce and market a product as a medical food than as a dietary supplement.

Comparison of Cyanocobalamin Formulations Oral Tablet Studies of cyanocobalamin have demonstrated differences in pharmacokinetics depending on the formulation examined. Berlin and colleagues conducted a longterm study in which the absorption of oral vitamin B12 was evaluated for up to 5 years among 64 patients.13 They found that approximately 56% of a 1-μg dose of oral cyanocobalamin was absorbed; however, absorption decreased dramatically when the intrinsic factor capacity was exceeded (approximately 1-2 μg of vitamin B12).13,14 The authors of the study demonstrated intrinsic factor– unrelated diffusion of 1.2% of any oral dose, and concluded that oral administration delivers much less cobalamin per dose if the intrinsic factor saturation point is exceeded, or if the patient has PA.13 Therefore, as a result of wide individual variation, ≥1000 μg must be taken daily to treat a vitamin B12 deficiency if malabsorption is the leading cause. Moreover, Berlin and colleagues concluded that absorption is decreased if oral cyanocobalamin is taken with a meal as opposed to fasting, with absorption rates of 1.8 μg to 7.5 μg versus 2.8 μg to 13.4 μg, respectively, for a 500-μg dose.13,14 Overall, this study illustrates some of the key absorptive issues related to dietary supplements of vitamin B12.13,14 Sublingual Tablets and Lozenges Although sublingual tablets and lozenges are often touted as having superior efficacy and bioavailability than other oral formulations, clinical evidence supporting this claim is lacking. However, studies have shown that the efficacy of both methylcobalamin and cyanocobalamin sublingual formulations is equal to that of oral tablets.15,16 Parenteral Formulations The pharmacokinetics of cyanocobalamin in IM, IV, and SC dosages has been examined in clinical trials.

Studies have shown that between 50% and 98% of an IM or SC dose of 100 μg to 1000 μg of cyanocobalamin is excreted unchanged in the urine, with the majority appearing within 8 hours after injection.8 Doses that exceed 100 μg will not result in significantly greater vita-

REVIEW ARTICLE

min B12 retention.17 However, liver stores may be replenished more quickly than with a lower dose.14,17 In addition, parenteral administration of cyanocobalamin at doses of 100 μg and 1000 μg are associated with a total body retention of 55% and 15%, respectively.17 The remaining 45% to 85% is excreted unchanged in the urine.17 The time to peak concentration (Tmax) for the IM injection is 1 hour. Specific data are not available for the Tmax of the SC injection, but are thought to be comparable to the IM injection.8 Nasal Spray Cyanocobalamin nasal spray, marketed as Nascobal (Endo Pharmaceuticals, Malvern, PA), is the only FDA-approved nasal spray to increase and maintain healthy levels of vitamin B12. It is administered once weekly. When studied in 25 healthy patients, peak concentrations occurred at 1.25 ± 1.9 hours. The bioavailability of the nasal spray relative to IM injection was found to be 6.1%. Therefore, the intranasal medication peaks quickly, but its overall efficacy compared with IM injection is questionable based on the low relative bioavailability.18 Cyanocobalamin/SNAC Oral Tablet The FDA designation of cyanocobalamin/SNAC as a medical food was based on 2 limited drug trials, including a pharmacokinetics study of oral formulations in 20 healthy men, and an efficacy and tolerability comparison of cyanocobalamin/SNAC with the current FDA-­ approved IM formulation.19,20 Study 1: Pharmacokinetics. In this study of 20 healthy men aged 20 to 45 years, cyanocobalamin/ SNAC had a more favorable pharmacokinetic profile than oral cyanocobalamin without SNAC.19 The 5-mg dose of cyanocobalamin/SNAC had a greater mean absolute bioavailability than the 5-mg commercial oral formulation (5.09% vs 2.16%, respectively). In addition, cyanocobalamin/SNAC reached an average peak plasma concentration (Cmax) of 12,847 pg/mL, whereas the Cmax for the commercial oral product was 1239 pg/mL. The Tmax was also lower for cyanocobalamin/SNAC (0.5 hours vs 6.83 hours for the commercial formulation).

The elimination half-life was similar:—30.06 hours for cyanocobalamin/SNAC versus 25.95 hours for the commercial formulation.19 Study 2: Efficacy and tolerability. The same investigators conducted a 3-month, randomized, multicenter trial in which 48 patients with vitamin B12 deficiency were randomly assigned to receive 1000 μg of oral cyanocobalamin/SNAC daily or 1000 μg of IM cyanocobalamin on study days 1, 3, 7, 10, 14, 21, 30, 60, and 90.20 The participants were required to be aged ≥60 years,

or ≥18 years with gastrointestinal abnormalities or with a restricted diet. The participants aged ≥60 years were not required to have gastrointestinal abnormalities or a restricted diet. The primary efficacy outcome was normalization of cobalamin levels (≥350 ng/mL) following 60 days of treatment, maintained through day 91 (the day following the last treatment). Both formulations were effective in restoring normal levels of serum cobalamin in all patients studied.20 The observed adverse effects were mild or moderate in intensity. Overall, 56.0% of study participants reported ≥1 adverse effects, all of which were transient. Among patients who received cyanocobalamin/SNAC, 54.2% reported ≥1 adverse effects. Of those who received IM cyanocobalamin, 57.7% reported ≥1 adverse effects.

These mild and moderate effects included constipation, diarrhea, nausea, fatigue, headache, back pain, and upper respiratory tract infection. Any adverse effects considered severe were deemed unrelated to the study medications. This study demonstrated that oral vitamin B12 formulated with SNAC is as safe and effective as IM injections of this vitamin.20

Discussion Many formulations are available for treating vitamin B12 deficiency, each with the common goal of increasing the levels of vitamin B12 in the bloodstream. IM injections of vitamin B12 typically have been the predominant delivery method for treating patients who require a rapid or highly bioavailable response. With cyanocobalamin/ SNAC, patients can receive a concentration level similar to that of injectable vitamin B12 without having to undergo injection. Cyanocobalamin/SNAC is the only once-daily oral prescription medical food tablet that has been shown to normalize vitamin B12 levels without the need for injection.21 Cyanocobalamin/SNAC was not shown to offer greater efficacy than IM vitamin B12, which is the current standard of care for hypocobalaminemia. However, cyanocobalamin/SNAC reached a higher Cmax than oral formulations of cyanocobalamin that do not contain SNAC, and its Tmax was only 30 minutes. (Another oral formulation took almost 7 hours to reach a lower Cmax.19) Cmax represents the peak concentration that a substance attains in the body and is reflective of systemic exposure.

The pharmacokinetics study was conducted exclusively in healthy men, which is problematic because women are twice as likely as men to develop vitamin B12 deficiency.19 Vitamin B12 deficiency can result from an abnormally functioning gastrointestinal tract. Patients aged between 40 and 70 years are often affected by vitamin B12 deficiency as normal aging occurs, and this population is likely to have a decrease in kidney function

A Novel Way to Treat Vitamin B12 Deficiency and Anemia

compared with younger adults (aged 20-45 years), who also participated in the 2 aforementioned studies. Furthermore, 15 of the 20 participants were African American; Caucasian and Latin American patients were poorly represented.19 As a result, this study may not be applicable to other races. Although few studies exist on this medical food, it will be interesting to see what the future holds for cyanocobalamin/SNAC and other novel medications that may include absorption promoters to increase mean concentration levels. In addition, more head-to-head trials should be conducted to compare the currently available cyanocobalamin medications with dietary supplements and with the medical food.

As is often true of new medications or medical foods, associated costs may be higher than those of existing treatments. Patients who receive injectable vitamin B12 can purchase a vial of cyanocobalamin for approximately $10, whereas the cost of cyanocobalamin/SNAC is approximately $45 for a 30-day supply. Moreover, there is a compliance concern regarding cyanocobalamin/ SNAC. Patients would be required to remember to take it daily, whereas IM maintenance injections are administered monthly, and the only FDA-approved nasal spray (Nascobal) is administered weekly.18 The cost of the cyanocobalamin nasal spray for patients who have commercial insurance is ≤$25 with a copay card from the manufacturer’s website. The price of the nasal spray for patients ineligible to receive the copay card exceeds $100 for a 1-month supply. Even though the price of the nasal spray with a copay card is cheaper than the price of cyanocobalamin/SNAC, studies have not shown that the bioavailability of the nasal spray is equivalent to that of the IM injection. Injection of cyanocobalamin is currently the most cost-effective treatment for patients with vitamin B12 deficiency, but cyanocobalamin/SNAC provides an oral option for patients who are not comfortable receiving injections.

Conclusion Cyanocobalamin/SNAC is a major advancement in the treatment of vitamin B12 deficiency, because it is the first product to include the absorption promoter SNAC. Cyanocobalamin/SNAC has been shown to have an absorption profile similar to that of injectable solutions of vitamin B12. Oral cyanocobalamin/SNAC and IM injections have been effective in restoring normal levels of serum cobalamin in all patients studied thus far.

In general, vitamin B12 deficiency is mild when discovered, and the etiology varies greatly. If untreated, serious conditions can occur, such as permanent nerve damage and anemia. Therefore, it is important to correct vitamin B12 levels as early as possible in patients with subclinical deficiency so that clinical deficiency

can be averted. The absorption of oral vitamin B12 dietary supplements and the nasal spray is not adequate to supply the amount of vitamin B12 needed to correct the deficiency, and IM or IV injection of cyanocobalamin can be painful and undesirable for certain patients.

Cyanocobalamin/SNAC represents a new treatment option that may be attractive for patients with vitamin B12 deficiency. n Author Disclosure Statement The authors have no conflicts of interest to report.

References

1. Carmel R. Prevalence of undiagnosed pernicious anemia in the elderly. Arch Intern Med. 1996;156:1097-1100.

2. Carmel R, Johnson CS. Racial patterns in pernicious anemia. Early age at onset and increased frequency of intrinsic-factor antibody in black women.

N Engl J Med. 1978;298:647-650.

3. Andrès E, Vogel T, Federici L, et al. Cobalamin deficiency in elderly patients: a personal view. Curr Gerontol Geriatr Res. 2008:848267.

4. Carmel R, Green R, Rosenblatt DS, Watkins D. Update on cobalamin, folate, and homocysteine. Hematology (Am Soc Hematol Educ Program). 2003:62-81.

5. Green R. Indicators for assessing folate and vitamin B-12 status and for monitoring the efficacy of intervention strategies. Am J Clin Nutr. 2011;94: 666S-672S. 6. Allen LH, Casterline J. Vitamin B-12 deficiency in elderly individuals: diagnosis and requirements. Am J Clin Nutr. 1994;60:12-14.

7. Gersten T. Anemia - B12 deficiency. MedlinePlus. www.nlm.nih.gov/med lineplus/ency/article/000574.htm. Updated February 24, 2014. Accessed June 22, 2015.

8. Cyanocobalamin injection, USP [package insert]. Schaumburg, IL: APP Pharmaceuticals, LLC; 2008.

9. Obeid R, Fedosov SN, Nexo E. Cobalamin coenzyme forms are not likely to be superior to cyano- and hydroxyl-cobalamin in prevention or treatment of cobalamin deficiency. Mol Nutr Food Res. 2015;59:1364-1372.

10. Eligen B12 (cyanocobalamin/SNAC) [package insert]. Roseland, NJ: Emisphere Technologies, Inc; 2014.

11. US Food and Drug Administration. Medical foods guidance documents & regulatory information. www.fda.gov/Food/GuidanceRegulation/Guidance DocumentsRegulatoryInformation/MedicalFoods/. Updated November 26, 2014.

Accessed September 5, 2015.

12. US Food and Drug Administration. Ingredients, packaging & labeling. www.fda.gov/Food/IngredientsPackagingLabeling/GRAS. Updated January 4, 2015. Accessed June 22, 2015.

13. Berlin H, Berlin R, Brante G, et al. Oral treatment of pernicious anemia with high doses of vitamin B12 without intrinsic factor. Acta Med Scand. 1968; 184:247-258.

14. Carmel R. How I treat cobalamin (vitamin B12) deficiency. Blood. 2008; 112:2214-2221.

15. Yazaki Y, Chow G, Mattie M. A single-center, double-blinded, randomized controlled study to evaluate the relative efficacy of sublingual and oral vitamin B-complex administration in reducing total serum homocysteine levels. J Altern Complement Med. 2006;12:881-885.

16. Sharabi A, Cohen E, Sulkes J, Garty M. Replacement therapy for vitamin B12 deficiency: comparison between the sublingual and oral route. Br J Clin Pharmacol. 2003;56:635-638.

17. Anon. Time to drop cyanocobalamin? Drug Ther Bull. 1984;22:43-44.

18. Nascobal (cyanocobalamin, USP) [package insert]. Spring Valley, NY: Par Pharmaceutical Companies, Inc; 2011.

19. Castelli MC, Wong DF, Friedman K, et al. Pharmacokinetics of oral cyanocobalamin formulated with sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC): an open-label, randomized, single-dose, parallel-group study in healthy male subjects. Clin Ther. 2011;33:934-945.

20. Castelli MC, Friedman K, Sherry J, et al. Comparing the efficacy and tolerability of a new daily oral vitamin B12 formulation and intermittent intramuscular vitamin B12 in normalizing low cobalamin levels: a randomized, openlabel, parallel-group study. Clin Ther. 2011;33:358-371.

21. Emisphere. Eligen B12. www.emisphere.com/eligen_b12.html. Accessed February 12, 2016.

ORIGINAL RESEARCH

Determination of Extended Sterility for Single-Use Vials Using the PhaSeal Closed-System Transfer Device Kristin V. Ho, PharmD, BCOP; Michael S. Edwards, PharmD, MBA, BCOP; Dominic A. Solimando, Jr, MA, BCOP; Anthony D. Johnson, CPhT

J Hematol Oncol Pharm.

2016;6(2):46-50 www.JHOPonline.com Disclosures are at end of text

T

Background: US Pharmacopeia (USP) Chapter 797 states that single-use vials may be used within 6 hours of initial puncture if maintained in an International Organization for Standardization 5 environment. The 6-hour standard is based on the microbial growth observed in various growth media under conditions specified in USP Chapter 71. However, studies have demonstrated that the PhaSeal closed-system transfer device (Becton, Dickinson and Company, Durham, NC) maintains sterility of unpreserved, single-use vials for ≤7 days. In these studies, the PhaSeal system was tested using growth media under simulated conditions. Extending the beyond-use date (BUD) of medications could reduce expenditures for medications, and help pharmacists cope with shortages of critical medications.

Objective: The purpose of this study was to confirm these results in actual practice, using an antineoplastic agent as the test solution.

Methods: In this prospective, observational study, fluorouracil aliquots were transferred to tryptic soy broth culture medium in intravenous bags over a 2-week period, using the PhaSeal system. Twelve aliquots and 96 bags were used. The bags and their contents were stored at 35°C for 14 days, and were monitored for evidence of microbial contamination.

Results: No microbial growth was observed throughout the 14-day period. Thus, at 336 hours (14 days), the probability of failure was 0% (95% confidence interval, 0-0.033).

Conclusion: The PhaSeal system maintains the sterility of unpreserved injectable solutions and can apparently be used to extend the BUD of single-use vials to ≥7 days. Findings support those of previous studies of PhaSeal’s utility in the reduction of medication waste, and the realization of significant cost-savings for parenteral medications.

he use of closed-system transfer devices (CSTDs) for compounding hazardous medications has become an accepted standard of practice to minimize environmental exposure to these agents.1 It has been reported that CSTDs can also preserve the sterility of unpreserved (single-use) medication vials.2-4 Maintaining sterility for prolonged periods may result in significant cost-savings through reduced drug waste.5,6 In a study of the cost-savings from using the PhaSeal CSTD (Becton, Dickinson and Company, Durham, NC) to extend the beyond-use date (BUD) of single-use vials, the potential savings were estimated to be

>$600,000 annually for 1 institution.5 A study of the actual savings achieved by using PhaSeal to extend the BUD of single-use vials demonstrated savings of $96,348.70 in <2 months, representing an annual saving of $703,047.67.6 In addition, using a CSTD to preserve the sterility of vials of parenteral medication may assist pharmacists in managing shortages of such drugs.6 Medication shortages can have an adverse impact on patient health. Of the 183 drug shortages reported in August 2015, 105 (57%) were of parenteral medications.7 Extending the BUD of parenteral drugs that are available in single-use vials is a

Dr Ho is an Oncology Pharmacist, Hematology-Oncology Pharmacy Service, Department of Pharmacy, Walter Reed National Military Medical Center, Bethesda, MD, and at the time this study was conducted, was an Oncology Pharmacy Resident (PGY2), Oncology Pharmacy Residency, Hematology-Oncology Pharmacy Service, Department of Pharmacy, Walter Reed National Military Medical Center, Bethesda, MD; Dr Edwards is a Consultant, Chevy Chase, MD, and at the time this study was conducted, was Director, Oncology Pharmacy Residency, Hematology-Oncology Pharmacy Service, Department of Pharmacy, Walter Reed National Military Medical Center, Bethesda, MD; Mr Solimando is President, Oncology Pharmacy Services, Inc, Arlington, VA, and Oncology Pharmacist, Hematology-Oncology Pharmacy Service, Department of Pharmacy, Walter Reed National Military Medical Center, Bethesda, MD; Mr Johnson is a Pharmacy Technician, Hematology-Oncology Pharmacy Service, Department of Pharmacy, Walter Reed National Military Medical Center, Bethesda, MD.

Determination of Extended Sterility for Single-Use Vials

possible means of minimizing shortages.

According to US Pharmacopeia (USP) Chapter 797, single-use vials must be used within 6 hours of being opened if maintained in an International Organization for Standardization (ISO) 5 environment, or within 1 hour if in a non–ISO 5 environment.8 The 6-hour standard is based on microbial growth observed in various growth media under conditions specified in USP Chapter 71, and aims to prevent patient harm by minimizing the impact of any microbial contamination.9,10 However, this standard was not established by direct testing of unpreserved vials under conditions of actual or simulated practice.

Specifically, USP Chapter 797 states that single-use vials exposed to an ISO 5 environment “…may be used up to 6 hours after initial needle puncture,” implying that a nonpreserved vial maintained in this environment could be used >1 time.8 This chapter also specifies that the BUD must be assigned “on the basis of direct testing or extrapolation from reliable literature sources and other documentation.”8 Strictly limiting the BUD to 6 hours can cause significant waste of costly medications or critical agents with limited availability.6 However, if a CSTD can maintain sterility of unpreserved vials for longer periods, it may be possible to extend the BUD of those vials. If using such a device ensures the sterility of these drugs so that all the contents of the vial can be used without harming the patient, then overall drug waste could be reduced substantially. Use of a CSTD to extend the BUD has been suggested to minimize the impact of drug shortages, as well as medication waste, and can result in significant cost-savings.5,6 A CSTD could potentially block the transfer of contaminants into the system, and, thus, maintain sterility of the medication. In a comparison study of 4 CSTDs, De Prijck and colleagues contaminated the protective coupling component (ie, injector or inlet) of each CSTD, and the rubber stoppers of vials with microorganism inoculation, and measured microbial contamination of the vials after multiple entries into each vial. All 4 systems demonstrated evidence of contamination if the vial stopper was not disinfected properly. Among the systems tested, PhaSeal was the most resistant to microbial contamination of the vial after repeated entries.2 Several studies have shown that the PhaSeal system maintains sterility of single-use vials for ≤7 days.3-5 McMichael and colleagues noted a contamination rate of 1.8% (6 of 332 samples) during the 168-hour study period; therefore, the probability that the vials would not be contaminated for ≤168 hours is 98.2%.3 Carey and colleagues reported a contamination rate of 0.3% during 168 hours, and an expected 99.7% probability that the vial would not be contaminated if manipulated by the same procedures, under the same environmental

conditions.4 Rowe and colleagues reported an overall contamination rate of 1.86% (11 of 592 samples had 1 colony-forming unit [cfu] on sheep blood agar or trypticase soy agar plates) for their 14-day study period.5 These studies were performed using sterile culture media under simulated conditions,3,4 or involved transfer of antineoplastic agents in an open system having greater potential for contamination.3,5 Although these studies were relatively small, the results were sufficient enough to convince the US Food and Drug Administration (FDA) to grant the ONB (Closed Antineoplastic and Hazardous Drug Reconstitution and Transfer System) product code to the PhaSeal system. The ONB product code is assigned to devices that have been certified as closed-system transfer units for use in compounding antineoplastic agents and other hazardous drugs. The code is awarded based on satisfying ≥2 of 3 criteria, which require the product to be leakproof (ie, no escape of hazardous drug or vapor concentration; no transfer of environmental contaminants), airtight, and preventive against microbial ingress.

The criteria used by the FDA to make this determination were: “no transfer of environmental contaminants,” and “prevention of microbial ingress.”11 Awarding of the ONB code to PhaSeal, coupled with evidence of the system’s effectiveness in preventing contamination and maintaining sterility of unpreserved single-use vials for ≤7 days,3,4 suggest that PhaSeal can be used to extend the BUD of medications without increasing the safety risk for patients. However, a limitation of the studies that show PhaSeal’s ability to maintain sterility is the test conditions, which were artificial.

The purpose of the current study was to test the effectiveness of the PhaSeal system in actual practice, using an antineoplastic agent as the test solution. Sterility monitoring was used as a measure of quality assurance for our compounding procedures.

Methods All tests were performed in the hematology-oncology pharmacy, in ISO 5 conditions using class II, type B2 biological safety cabinets (BSCs) and personal protective equipment, in compliance with all requirements of USP Chapter 797.8 The BSCs were certified according to NSF/ANSI-49 specifications to ensure compliance with USP Chapter 797 requirements. All PhaSeal devices were attached in accordance with the manufacturer’s instructions in the ISO 5 cleanroom.

Hands were washed, and sterile gloves were donned and sanitized prior to work in the BSC. The PhaSeal protector, adapter, and injector were placed in the BSC. In accordance with USP Chapter 797 standards, the work surface, syringes, intravenous (IV) bags, fluorouracil vials, and PhaSeal components were sanitized with

ORIGINAL RESEARCH

Table R esults of Turbidity Observation Time (hours) Vial

0

6

24

48

72

120

168

336

1

No

No

No

No

No

No

No

No

2

No

No

No

No

No

No

No

No

3

No

No

No

No

No

No

No

No

4

No

No

No

No

No

No

No

No

5

No

No

No

No

No

No

No

No

6

No

No

No

No

No

No

No

No

7

No

No

No

No

No

No

No

No

8

No

No

No

No

No

No

No

No

9

No

No

No

No

No

No

No

No

10

No

No

No

No

No

No

No

No

11

No

No

No

No

No

No

No

No

12

No

No

No

No

No

No

No

No

(–) Control

No

No

No

No

No

No

No

No

(–) Control

No

No

No

No

No

No

No

No

(+) S aureus

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

(+) E coli

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

E coli indicates Escherichia coli 25922; S aureus, Staphylococcus aureus 6538.

sterile, 70% isopropyl alcohol before being placed in the BSC. Labels consecutively numbered with “0 hours, vial number” were affixed to the front of each 100-mL tryptic soy broth (TSB) IV bag. Matching numbered labels were affixed to 100-mL fluorouracil and positive control vials or sample vials. The IV bags, vials, and equipment were placed in the BSC by an assistant, which precluded the operator from having to remove his or her hands from the BSC; this expedited the test process. The assistant also placed new test materials in the BSC, and removed used bags and storage vials. The operator resanitized his or her gloved hands after every 3 preparations, or whenever he or she touched items outside the BSC. The TSB bag was placed on the work surface. The cap was removed from the matching numbered 100-mL fluorouracil vial. The vial septum was sanitized by wiping once with sterile, 70% isopropyl alcohol from the septum across the aluminum rim, in a unidirectional motion. The alcohol was allowed to dry for ≥10 seconds.

The PhaSeal protector was removed from its wrapper aseptically by touching only the expansion bell or cap.

The injection port remained sterile. The cap of the PhaSeal protector was aseptically removed from the device, and the protector was attached to the vial. The

cap covering the set port of the IV bag was removed, and the port was sanitized with sterile, 70% isopropyl alcohol. A PhaSeal infusion adapter was aseptically removed from its sterile packaging and inserted into the port on the TSB bag. Ten mL of air were drawn into a 20-mL syringe, to which the PhaSeal injector was attached. The syringe-injector combination was attached to the vial, and 10 mL of fluorouracil was withdrawn.

The syringe-injector combination was detached from the vial-protector combination, and was attached to the port on the infusion adapter, which had been attached to the TSB bag. The contents of the syringe were injected into the TSB bag. The injector-syringe assembly was disconnected from the infusion adapter–IV bag assembly and discarded.

The protector-fluorouracil vial combination was placed in an amber plastic bag for light protection, and stored in the ISO 5 room to minimize contamination.

The procedure was repeated at 6 hours, and on days 1 (24 hours), 2 (48 hours), 3 (72 hours), 5 (120 hours), 7 (168 hours), and 14 (336 hours). The TSB bags containing fluorouracil or a positive control were incubated at 35°C for 14 days, and monitored daily for evidence of microbial contamination based on the appearance of turbidity.

Determination of Extended Sterility for Single-Use Vials

A total of 12 fluorouracil vials were tested among 96 TSB bags. The 2 positive controls were Staphylococcus aureus 6538 and Escherichia coli 25922 (each 100 cfu/mL, obtained from the American Type Culture Collection).

Two unopened TSB bags served as negative controls.

Results No evidence of microbial contamination was noted in any test sample (Table). This indicates that, at 336 hours (14 days), the probability of failure (ie, contamination) was 0% during the transfer of fluorouracil to TSB IV bags (95% confidence interval, 0-0.033).

The TSB culture bags were inoculated with 1 mL of the organism, and incubated at 35°C. The 2 negative controls showed no visual evidence of microbial contamination or turbidity after 72 hours, or at 14 days of incubation (Table). The positive controls showed growth at 48 hours. Crystallization was observed in 4 of the 12 fluorouracil vials after 1 week of storage at 22°C. The crystallization was attributed to a lower-than-usual room temperature, and not believed to be related to the sterility of the preparations or testing procedure.

Discussion Our findings support the notion that the PhaSeal system maintains the sterility of parenteral solutions and allows extension of the BUD of single-use vials to ≥7 days.

Our results are similar to those of McMichael, Carey, and their respective colleagues, who demonstrated that PhaSeal is capable of maintaining sterility of single-use vials in a controlled environment for ≤168 hours.3,4 Although our study was based solely on sterility findings, the chemical stability of the drug must also be considered. If a drug’s chemical stability is limited, the ability to extend the BUD will be limited as well. For example, solutions of cyclophosphamide reconstituted with saline (20 mg/mL) are stable for 6 days if refrigerated at 2°C to 8°C.12 Even though the PhaSeal system would maintain the sterility of the solution for 7 days, any unused cyclophosphamide solution would need to be discarded after 6 days. Conversely, commercially available fluorouracil solutions (50 mg/mL) typically have expiration dates of ≥1 years. In our study, sterility was assessed for only 14 days; therefore, based on our findings, the BUD for fluorouracil should not exceed 14 days.

Additional studies are warranted to confirm our results and examine whether sterility could be maintained for a longer period.

Despite our findings, we recommend a BUD of 7 days, as previously reported.13 Although Martel and colleagues reported that the stability of fluorouracil in polyvinyl chloride bags is unaffected through 14 days of storage at 4°C or 21°C, they found visual evidence of

flocculent precipitate in several vials after 5 days of storage in an ISO 5 environment.13 Heating (to 60°C) and vigorous shaking of the vial often dissolves the precipitate.14 A potential confounding factor would be any antimicrobial activity of the fluorouracil itself. Some antineoplastic agents may exhibit low-level activity against indigenous human microflora, and/or opportunistic pathogens.15,16 This antimicrobial activity is not directed against any specific microbial agent,15 and is unlikely to preclude the recovery of bacteria by standard culture techniques.16

Limitations The major limitations of our study are the small sample size, use of only 1 culture medium, visual determination of contamination, and testing of only 1 drug. The small sample size did not provide sufficient power to detect possible statistical differences or significance, potentially leading to a type II error (false-negative result).

Because only 1 culture medium was used, detection of contamination was limited to organisms that can grow in that particular medium. Our findings for fluorouracil may not reflect the stability of other drugs subjected to similar conditions.

Determining contamination by visual inspection may be inferior to inoculating and incubating plates of growth media. Visual examination was chosen over plating for 2 reasons: we desired to maintain a completely closed system to eliminate any possibility of an additional source of contamination, which might confound our results, and did not have support from the microbiology laboratory for processing samples of a hazardous agent. Based on our findings, we recommend routine monitoring of sterility in partially used vials by sampling the contents during and after compounding sterile dosage forms of medications.

Conclusion Under conditions that resemble an actual practice setting, it appears that the PhaSeal system maintains the sterility of parenteral solutions, and allows extension of the BUD of single-use vials to ≥7 days. This supports previous recommendations for using the PhaSeal system to reduce the impact of drug shortages, decrease medication waste, and significantly increase cost-savings. n Author Disclosure Statement Dr Ho, Mr Solimando, and Mr Johnson reported no conflicts of interest; Dr Edwards is on the Speakers Bureau for Celgene, Millennium, SeattleGenetics, Merck, Astellas, and Onyx.

The opinions or assertions contained herein are the private views of the authors, and are not to be construed

ORIGINAL RESEARCH

as official, or reflections of, the views of the US Department of the Army, US Department of the Navy, or US Department of Defense.

References

1. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. www.ashp.org/DocLibrary/BestPractices/PrepGdlHaz Drugs.aspx. Accessed July 2, 2015.

2. De Prijck K, D’Haese E, Vandenbroucke J, et al. Microbial challenge of four protective devices for the reconstitution of cytotoxic agents. Lett Appl Microbiol.

2008;47:543-548.

3. McMichael DM, Jefferson DM, Carey ET, et al. Utility of the PhaSeal closed system drug transfer device. Am J Pharm Benefits. 2011;3:9-16.

4. Carey ET, Forrey RA, Haughs D, et al. Second look at utilization of a closed-system transfer device (PhaSeal). Am J Pharm Benefits. 2011;3:311-318.

5. Rowe EC, Savage SW, Rutala WA, et al. Economic and microbiologic evaluation of single-dose vial extension for hazardous drugs. J Oncol Pract. 2012;8: e45-e49.

6. Edwards MS, Solimando DA Jr, Grollman FR, et al. Cost savings realized by use of the PhaSeal® closed-system transfer device for preparation of antineoplastic agents. J Oncol Pharm Pract. 2013;19:338-347.

7. American Society of Health-System Pharmacists. Drug shortages: current

drugs. www.ashp.org/menu/DrugShortages/CurrentShortages. Accessed July 2, 2015.

8. Pharmaceutical compounding—sterile preparation. In: The United States Pharmacopeia, 34th rev., and The National Formulary, 29th ed. Rockville, MD: United States Pharmacopeial Convention; 2011:336-373.

9. Sterility tests. In: The United States Pharmacopeia, 34th rev., and The National Formulary, 29th ed. Rockville, MD: United States Pharmacopeial Convention; 2011:65-70.

10. Cundell A. Review of the media selection and incubation conditions for the compendial sterility and microbial limit tests. Pharm Forum. 2002;28:2034-2041.

11. US Food and Drug Administration. Product classification. www.accessdata. fda.gov/scripts/cdrh/cfdocs/cfPCD/classification.cfm?ID=2535. Accessed July 13, 2015.

12. Trissel LA. In: Handbook on Injectable Drugs, 17th ed. Bethesda, MD:American Society of Health-System Pharmacists; 2013: 313-318.

13. Martel P, Petit I, Pinguet F, et al. Long-term stability of 5-fluorouracil stored in PVC bags and in ambulatory pump reservoirs. J Pharm Biomed Anal. 1996;14: 395-399.

14. Trissel LA. In: Handbook on Injectable Drugs, 17th ed. Bethesda, MD:American Society of Health-System Pharmacists; 2013:523-530.

15. Hamilton-Miller JMT. Antimicrobial activity of 21 anti-neoplastic agents.

Br J Cancer. 1984;49:367-369.

16. Bodet CA III, Jorgensen JH, Drutz DJ. Antibacterial activities of antineoplastic agents. Antimicrob Agents Chemother. 1985;28:437-439.

REVIEW ARTICLE SERIES

Overview of the Recent Developments in Chronic Lymphocytic Leukemia, Part 1 Austin J. Combest, PharmD, BCOP, MBA; Ryan C. Danford, PharmD; Elizabeth R. Andrews, PharmD; Ashley Simmons, PharmD; Paulina McAtee, PharmD; Dirk J. Reitsma, MD É

The full Review Article is available now at JHOPonline.com

J Hematol Oncol Pharm.

2016;6(2):54-56 www.JHOPonline.com Disclosures are at end of text

Background: The clinical development landscape for chronic lymphocytic leukemia (CLL) is evolving rapidly, and continuously challenges current therapeutic guidelines. Several new agents have recently gained approval from the US Food and Drug Administration and European Medicines Agency, including venetoclax, ibrutinib, idelalisib, and obinutuzumab. These new therapies, together with recent updates to the guidelines from the National Comprehensive Cancer Network and European Society for Medical Oncology, reflect findings of improved progression-free and overall survival rates, and represent a new age in the treatment of CLL. Objective: The objective of this manuscript is to provide an overview of recent changes to the CLL landscape, as well as future directions to inform practitioners and clinical researchers.

Discussion: Because of these changes, it is likely that the future will bring further development of niche drugs that target cytogenetic abnormalities—specifically 11q and 17p—as well as more active and tolerable regimens for older patients. Tolerable regimens and convenient routes of administration are needed to enable outpatients to self-administer their treatment long-term, and improve their quality of life.

Conclusion: The increasing number of novel agents for CLL management present new challenges for appropriate sequencing of these agents, and comparator arm choices for future trials.

Collaboration between developers can lead to more efficient and less costly clinical trials. Increased enrollment in clinical trials, especially among older patients, will be critical for the continued development of novel agents in the treatment of CLL.

F

rom 2005 to 2014, the number of ongoing trials of chronic lymphocytic leukemia (CLL) has increased at a compound annual growth rate of 18.4%.1 This rapid growth in the CLL clinical trial landscape has led to multiple breakthroughs in the management of CLL, which have changed—and will continue to change— the treatment paradigm in the near future. One major breakthrough includes the discovery and development of agents targeting the B cell. CLL pathogenesis is a complex process that results in replication of malignant B lymphocytes. B-cell receptor signaling plays a role in B-cell survival and proliferation in CLL through the actions of protein kinases. The cells of CLL reportedly have high levels of B-cell receptor signaling activity.2 Dr Combest is Senior Director of Clinical Science at Pharmaceutical Product Development (PPD), Department of Global Product Development, Wilmington, NC, and Director of the University of North Carolina/PPD drug development fellowship, Chapel Hill. Dr Danford is a Staff Pharmacist at CVS, Burlington, NC. Dr Andrews is a drug development fellow at PPD. Dr Simmons is an Associate Director of Clinical Operations at Parion Sciences, Raleigh-Durham, NC. Dr McAtee is an Associate Director of Clinical Pharmacy Services at PPD. Dr Reitsma is Vice President and head of oncology at PPD.

Bruton tyrosine kinase (Btk) and phosphoinositide 3-kinase delta play important roles in this signaling process once the B-cell receptor is ligated. Once Btk is activated by the Src family kinases (Blk, Lyn, and Fyn), it activates phospholipase-Cγ through phosphorylation, which mobilizes internal calcium and activates the NF-κB and mitogen-activated protein kinase pathways.

People with mutations in Btk have low levels of B cells and immunoglobulins. Inhibiting these kinases has demonstrated practice-changing efficacy in CLL.3 With a better understanding of B-cell receptor signaling pathways, treatment and research focus has shifted from alkylating agents and purine analogs to alternate approaches, including targeting tyrosine kinase inhibitors and novel anti-CD20 monoclonal antibodies, which interfere with B-cell signaling. This transition has revolutionized CLL to a disease that is manageable, allowing some patients with the condition to live a normal life­ span. Ongoing trials are designed to demonstrate the optimal combinations and sequences of treatments, with the possibility of developing a curative regimen for select patients.

Several novel agents have recently received breakthrough therapy designation and subsequent approval from the US Food and Drug Administration (FDA). By the end of 2014, 17 medications designated as break-

Overview of Recent Developments in CLL, Part 1

through therapies had gained FDA approval; 11 were approvals in hematology and oncology, with 4 indicated for patients with CLL. The latter include ibrutinib (Imbruvica; Pharmacyclics LLC, Sunnyvale, CA), idelalisib (Zydelig; Gilead Sciences, Inc, Foster City, CA), ofatumumab (Arzerra; Novartis Pharmaceuticals Corporation, East Hanover, NJ), and obinutuzumab (Gazyva; Genentech, Inc, South San Francisco, CA).4 Ibrutinib received FDA approval in February 2014 for the treatment of patients with CLL who have received ≥1 previous therapies; in July 2014, accelerated approval was granted for a new indication: patients with CLL with 17p deletion/ mutation (del17p). In March 2016, an additional expanded approval was granted to ibrutinib for the first-line treatment of CLL.5 At the same time, idelalisib received FDA approval for the treatment of relapsed CLL in combination with rituximab. In April 2014, the anti-CD20 monoclonal antibody ofatumumab was granted FDA approval to expand its use to patients with untreated CLL for whom fludarabine-based therapy is inappropriate. The CD20-directed cytolytic antibody, obinutuzu­ mab, gained approval in November 2013 for frontline treatment of patients with CLL in combination with chlorambucil. All 4 agents also received approval from the European Medicines Agency 2 to 3 months after the FDA approval. In addition, in April 2016, the FDA granted accelerated approval of venetoclax, a Bcl-2 inhibitor, for patients with CLL with del17p, and who have been treated with ≥1 prior therapies.6 Although these breakthrough therapies have dramatically improved outcomes, their cost to patients and society is not insignificant. Ibrutinib and idelalisib are oral medications that require continuous and indefinite daily use. The average wholesale price for a 12-month supply of these agents is approximately $118,000.7 Because CLL is considered a disease of older adults, oral medications are covered by Medicare Part D in the United States.

However, there are coverage gaps requiring significant out-of-pocket expenses, estimated to be $20,847 for a 30-month course of ibrutinib, and $14,449 for a 20month course of idelalisib in the relapsed setting. The average wholesale price of obinutuzumab plus chlorambucil is $52,877 for 6 cycles of therapy; however, because obinutuzumab is an intravenous medication, it is covered

by Medicare Part B in the United States, which does not have the same coverage gap as Part D. The estimated out-of-pocket expense for obinutuzumab and chlorambucil is $1179. Ofatumumab’s average wholesale price is $124,332 for 6 cycles of therapy; however, because it is an intravenous medication, the out-of-pocket costs for patients with Medicare Part B are not significant. In the future, it is expected that idelalisib and ibrutinib will gain broad approval as first-line treatment of CLL, which will

Incidence and 3-Year Figure Chronic Lymphocytic Leukemia Prevalence Worldwidea,b Western Europe Southern Europe Northern Europe

n CLL 3-year prevalence n CLL incidence

Central and Eastern Europe Asia Northern America 0

5000

10,000

15,000

20,000

Number of Patients a CLL incidence comprises the absolute number of cases annually.

Three-year prevalence represents the number of CLL patients diagnosed and alive after 3 years. b To determine CLL epidemiology, this analysis includes WHO GLOBOCAN 2012 data. However, CLL epidemiology is not referenced in GLOBOCAN; therefore, the proportion of CLL case incidence and 3-year prevalence was calculated. CLL comprises approximately 30% of leukemia cases in Western countries and ~4%-10% of leukemia cases in Asia.

CLL indicates chronic lymphocytic leukemia.

Source: Reference 16.

lead to an even greater cost burden for the patient. Outof-pocket costs in Europe vary, with some medications undergoing pharmacoeconomic evaluation before becoming available (as is done by the National Institute for Health and Care Excellence in the United Kingdom).

This increase in approvals has created a dynamic clinical development landscape for CLL, including increasing competition of promising agents, a change in the standard of care, and more challenging regulatory hurdles. Sequencing, and the ideal combinations of novelnovel or novel-approved regimens, are considerations for future clinical trials. These new therapies have demonstrated better progression-free and overall survival rates than those of traditional chemotherapy regimens. Although these improvements bring hope to patients and practitioners, they also create challenges for future CLL drug development. The competition has increased the threshold for expected CLL efficacy and approval for future agents, because they will be compared with these newer agents. Thus, future studies are warranted to explore biomarkers or other surrogate end points, such as minimal residual disease status, which may further guide treatment and differentiate marketed products. Cytogenetics may also play an important role in future trials and their ability to identify the best drug for each patient. To address these challenges, collaborative efforts among pharmaceutical companies may be a novel and necessary direction of future CLL research.

REVIEW ARTICLE SERIES

Part 1 of this review was undertaken to provide better understanding of the future of CLL research. Our objective for the remainder of the series is to characterize CLL and its current treatments, compare newly approved drugs to traditional regimens, identify promising medications in development, and explore potential implications for CLL drug development.

Global Epidemiology of Chronic Lymphocytic Leukemia CLL is the most common leukemia in Western countries, representing approximately 22% to 30% of all leukemias worldwide.8,9 In certain Asian countries (eg, China, India, and Japan), the percentage of CLL cases is much lower (4%-10% of leukemias).10-14 However, these countries have large populations, so the actual number of afflicted patients might be similar. The global annual incidence is between <1 and 5.5 per 100,000 people, and more men than women are affected.10 The incidence of CLL is approximately 4.2 cases per 100,000 people in the Western world.9,15 The global CLL incidence and 3-year prevalence are shown in the Figure.16 This figure also shows that few countries have a large population with CLL, which brings to light potential challenges that arise when selecting countries and sites for studying CLL, especially in phase 3 trials. In addition to the low incidence/prevalence, there is intense competition for these patients. n Author Disclosure Statement Dr Combest, Dr McAtee, and Dr Reitsma are employees of Pharmaceutical Product Development (PPD), Wilmington, NC. Dr Danford is a Research Fellow at PPD, and the University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC. Dr Andrews and Dr Simmons have no relevant disclosures to report.

References

1. Citeline: TrialTrove. https://ppd.citeline.com/default.asp. Accessed January 2015.

2. Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood. 2012;120:1175-1184.

3. O’Brien SM. Therapy for chronic lymphocytic leukemia. Am Soc Clin Oncol Educ Book. 2010:273-278.

4. US Food and Drug Administration. Breakthrough therapy approvals. www. fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandAp proved/DrugandBiologicApprovalReports/NDAandBLAApprovalReports/ ucm373418.htm. Accessed May 16, 2016.

5. US Food and Drug Administration. All approvals March 2016. www.access data.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Reports.Monthly ApprovalsAll. Accessed May 11, 2016.

6. US Food and Drug Administration. FDA approves new drug for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm495253.htm.

Updated April 11, 2016. Accessed May 11, 2106.

7. Shanafelt TD, Borah BJ, Finnes HD, et al. Impact of ibrutinib and idelalisib on the pharmaceutical cost of treating chronic lymphocytic leukemia at the individual and societal levels. J Oncol Pract. 2015;11:252-258.

8. Siegel R, Naishadham D, Ahmedin J. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10-29.

9. Surveillance, Epidemiology, and End Results (SEER) Program Research Data (1973-2012), National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch. http://seer.cancer.gov/data/. Published April 2015. Accessed May 2, 2016.

10. Redaelli A, Laskin BL, Stephens JM, et al. The clinical and epidemiological burden of chronic lymphocytic leukaemia. Eur J Cancer Care (Engl). 2004;13: 279-287.

11. Gogia A, Sharma A, Raina V, et al. Assessment of 285 cases of chronic lymphocytic leukemia seen at single large tertiary center in Northern India.

Leuk Lymphoma. 2012;53:1961-1965.

12. Zheng W, Linet MS, Shu XO, et al. Prior medical conditions and the risk of adult leukemia in Shanghai, People’s Republic of China. Cancer Causes Control. 1993;4:361-368.

13. Kobayashi T, Kita K, Ohno T, Shirakawa S. Chronic lymphocytic leukemia in Japan. Rinsho Ketsueki. 1990;31:554-563.

14. Hernandez JA, Land KJ, McKenna RW. Leukemias, myeloma, and other lymphoreticular neoplasms. Cancer. 1995;75(1 Suppl):381-394.

15. Eichhorst B, Hallek M, Dreyling M. Chronic lymphocytic leukaemia: ESMO clinical practice guidelines for diagnosis, treatment, and follow-up. Ann Oncol. 2010;21(Suppl 5):v162-v164.

16. Leukaemia—estimated incidence and prevalence, adult population: both sexes. GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. http://globocan.iarc.fr/old/summary_table_site_prev. asp?selection=12280&title=Leukaemia&sex=0&africa=1&america=2&asia=3 &europe=4&oceania=5&build=6&window=1&sort=0&submit=%C2%A0 Execute%C2%A0. Published 2012. Accessed May 16, 2016.

FROM THE LITERATURE

Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy With Commentaries by Robert J. Ignoffo, PharmD, FASHP, FCSHP Clinical Professor Emeritus, University of California, San Francisco; Professor of Pharmacy, College of Pharmacy, Touro University–California, Mare Island, Vallejo, CA

n Personalizing Therapy for Patients with Multiple Myeloma BACKGROUND: Multiple myeloma is no different from other cancers that have wide variations in their genetic and mutation profiles. Many subsets of patients with multiple myeloma exist, with different biologic drivers and patient-specific characteristics that impact therapeutic efficacy. Understanding the patient’s genetic and functional status can therefore help in tailoring patient-specific treatment regimens.

METHODS: As part of a review article, investigators discuss the role of functional status and genetics to help guide therapeutic decisions for patients with multiple myeloma and improve patient outcomes.

RESULTS: The genetic landscape of this disease is complicated—involving from 5 to 20 different genotypes—therefore, assessing each patient carefully for functional and genetic status may help improve outcomes. Functional assessment in a patient with multiple myeloma is an important early driver, because it determines the intensity of therapy. Traditionally, functional status was used to determine if a patient should undergo autologous stem cell transplant (SCT) as part of the initial therapy. The authors argue that this may not be necessary, because evidence shows that patients aged ≥70 years can undergo transplant as long as they receive a lower dose of melphalan chemotherapy during the transplant process.

A patient’s frailty may be more important when deciding on an initial treatment regimen that includes either an intensive triplet therapy or less intensive with only doublet therapy. For patients fit enough for a transplant, the authors recommend initial triplet therapy with lenalidomide (Revlimid), bortezomib (Velcade), and the corticosteroid dexamethasone, followed by transplant. By contrast, for older patients who are frail, they note that evidence from recent clinical trials suggests that a 2-drug regimen is better tolerated in this patient population and has equivalent outcomes to triplet therapy. Genomic profile can also be used to tailor therapy to the individual patient with multiple myeloma. Evolving molecular diagnostic tests, such as targeted gene sequencing, RNA sequencing, or copy

number arrays, can facilitate a more accurate stratification of patients. In transplant-eligible newly diagnosed patients with multiple myeloma, Dr Lonial and Dr Nooka recommend intensive induction triplet therapy with lenalidomide, bortezomib, and dexamethasone, and continued triplet maintenance therapy for patients with high-risk disease at diagnosis; for standard-risk patients, they recommend lenalidomide-only maintenance therapy. Patients with newly diagnosed disease who are too frail to undergo an SCT and have standard-risk disease, can receive doublet therapy with lenalidomide and dexamethasone or with bortezomib and dexamethasone. However, newly diagnosed patients with high-risk disease should receive a modified dose of lenalidomide, bortezomib, and dexamethasone triplet therapy.

“The use of an optimal induction regimen followed by high-dose therapy does not limit the ability to tailor therapy to patients,” the experts note. “Once the initial induction and consolidation (with a transplant) are complete, there are likely to be opportunities to tailor therapy in the maintenance phase on the basis of genetics.”

As for future directions on how to tailor treatments for multiple myeloma, they conclude, “The current literature suggests that the use of biology-driven treatments, taking into account functional status and genetics, is likely the first and most important step. The incorporation of these agents with biology-based approaches will likely yield the best and most effective treatments as we continue to learn how best to target the many mutations found in patients with myeloma.”

Source: Lonial S, Nooka AK. Myeloma is not a single disease.

J Oncol Pract. 2016;12:287-292.

COMMENTARY BY ROBERT J. IGNOFFO

This clinical review highlights important considerations when making decisions about primary, induction, and maintenance therapy. Improvement

FROM THE LITERATURE

COMMENTARY BY ROBERT J. IGNOFFO

in overall and progression-free survival has been shown with SCT, and the use of a 3-drug induction regimen. Furthermore, an immunomodulatory drug plus a proteasome inhibitor combined with dexamethasone is the preferred 3-drug induction regimen because it has a greater likelihood of inducing a complete remission and leading to a curative transplant. However, whether a patient can receive an SCT or a 3-drug induction regimen often depends on a patient’s functional, cytogenetic, and mutational status.

Myeloma presents with a wide variety of mutations, leading to variable survival and response characteristics. The use of patient functional status and cytogenetics should be considered when making therapeutic decisions about induction and maintenance therapy, especially in frail patients. The authors stress that functional performance status is more important than chronologic age, and recommend the use of measurement tools, such as the Frailty Index, to guide the clinician in selecting appropriate therapy.

(71%), and those with unmutated IGHV (76%). The researchers also estimated the 15-month progression-free survival rate to be 69% with the expansion dose. In terms of safety, tumor lysis syndrome occurred in 10 patients in the dose-escalation group, but clinically impor­ tant sequelae occurred in only 3 of those patients, 2 of whom had severe sequelae. After adjustments were made to the dosing schedule, no incidences of tumor lysis syndrome occurred in the expansion cohort. Other adverse events included mild diarrhea, upper respiratory tract infection, nausea, and grade 3 or 4 neutropenia, which occurred in 41% to 52% of patients. This first trial of venetoclax demonstrates the potential of BCL2 antagonism as an additional therapy for patients with relapsed CLL, including those with poor prognostic features.

Furthermore, the overall response rate in patients provides support for investigating venetoclax as a treatment option for patients with heavily pretreated relapsed or refractory small lymphocytic lymphoma, concluded the researchers.

Source: Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:311-322.

COMMENTARY BY ROBERT J. IGNOFFO

n Targeting BCL2 with Venetoclax in Patients with Relapsed CLL BACKGROUND: Targeted therapies have improved the outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but achieving complete remission remains uncommon. Venetoclax is an investigational inhibitor of B-cell lymphoma-2 receptor (BCL2), which is a protein that is central to the survival of CLL cells.

METHODS: A total of 116 patients were enrolled in the study; 56 patients in the dose-escalation cohort received active treatment in 1 of 8 dose groups that ranged from 150 mg to 1200 mg daily; in an expansion cohort, 60 patients were treated with venetoclax in a weekly stepwise ramp-up dosing of up to 400 mg daily.

RESULTS: The majority of patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Patients receiving venetoclax had an overall response rate of 79% and a complete response rate in 20% of patients, including 5% who had no minimal residual disease by flow cytometry. Venetoclax was active at all dose levels, and no maximum tolerated dose was identified. Among patients with an adverse prognosis, the response rates ranged from 71% to 79% depending on the subgroup, including those with resistance to fludarabine (79%), chromosome 17p deletions

CLL is a chronic disease that primarily occurs in elderly patients. It is well known that treating elderly patients with cytotoxic agents is difficult because of the high frequency of life-threatening toxicities, especially febrile neutropenia. According to the National Comprehensive Cancer Network (NCCN) guidelines, ibrutinib and idelalisib in combination with rituximab are the standard of care for patients with refractory CLL. Venetoclax was developed to effectively inhibit the BCL2 receptor while having little effect on platelets. However, it has been associated with several adverse events, including diarrhea, upper respiratory infection, and neutropenia in 40% to 50% of patients. Grade 4 neutropenia also occurred in half of patients, but was controlled with a granulocyte colony-stimulating factor. Fortunately, febrile neutropenia occurred in <20% of patients. This phase 1 study produced approximately 80% partial and complete responses at all dose levels in patients with refractory CLL— even those with poor prognostic features, and aged ≤86 years. These impressive results have led the NCCN to update its latest guideline to include venetoclax as a first-line agent for the treatment of patients with refractory CLL.