BUSULFAN PLASMA EXPOSURE UNIT (BPEU) HARMONIZATION - JEANNINE S. MCCUNE, PHARMD, BCOP PROFESSOR, CITY OF HOPE FEBRUARY 2020

Busulfan Plasma Exposure
Unit (BPEU) Harmonization

 Jeannine S. McCune, PharmD, BCOP
 Professor, City of Hope
 February 2020

Financial Disclosures

• None
• Off label use of busulfan is mentioned

 2

Acknowledgements

• Steering Committee: Lee Dupuis, Jeannine McCune, James Ritchie, Erik van
 Maarsveen, Rosa Yeh
• Expert Panel: Claudio Anasetti, Jaap Boelens, Nelson Hamerschlak, Moustapha
 Hassan, Hyoung Jin Kang, Yoshinobu Kanda, Angelo Paci, Peter J. Shaw,
 Mohamed Mohty
• All 38 members of the Task Force
• Support of the ten professional societies that endorsed this busulfan
 harmonization, particularly ASTCT Clinical Practice Guideline Committee

 3

Learning Objectives

• List benefits of unit harmonization for busulfan exposure
• Convert commonly used busulfan exposure units to the harmonized unit
• Describe available tools and literature to support institutional use of the
 harmonized unit

 4

Most Conditioning Regimens for AML/MDS Include Busulfan

 Myeloablative Reduced Intensity
 Conditioning (MAC) Conditioning (RIC)

 >66% include busulfan >33% include busulfan

 Bu: busulfan; Cy: cyclophosphamide; Flu: fludarabine;
D'Souza A, Fretham C. Current Uses and Outcomes of Hematopoietic Cell Transplantation (HCT):
CIBMTR Summary Slides, 2018. Available at https://www.cibmtr.org. Accessed 17 January 2020 TBI: total body irradiation; Mel: melphalan
 5

Busulfan in HCT

• Alkylating agent that is FDA approved for treating chronic myeloid leukemia alone
 (oral busulfan, 1953) or with cyclophosphamide (BU/CY) conditioning for
 allogeneic HCT (IV busulfan, 1999)
• Dose limiting toxicity is sinusoidal obstruction syndrome (SOS)
• 1989 – 1997: Early pharmacodynamic associations reported with BU/CY
• 1996 – present: Therapeutic drug monitoring or pharmacokinetic (PK)-directed
 dosing of busulfan
 —↑ engraftment rates from 74% to 96% (N=32)1
 —↓ hepatotoxicity (VOD/SOS) rates from 75% to 18% (N=27)2
 —↓ relapse rates in chronic phase chronic myeloid leukemia (before imatinib)3

1BolingerAM, et al. Bone Marrow Transplant. 2001;28(11):1013-1018.
2Grochow LB. Semin Oncol. 1993;20(4 Suppl 4):18-25. HCT: hematopoietic cell transplantation
3Radich JP, et al. Blood. 2003;102(1):31-35.

 VOD: veno-occlusive disease
 6

PK-directed Busulfan Dosing
 • First dose based on body
 10000 surface area (BSA) or body
 weight
 1000 • Get multiple blood samples to
 Busulfann (ng/mL)

 estimate area under the curve
 (AUC)
 100 • Clearance = dose divided by
 AUC
 • Know target AUC
 10
 • Adjust dose based on patient’s
 clearance to achieve target
 1 AUC
 0 60 120 180 240 300 360 420
 Time (min)

 7

Variability in Target Exposure in Children with AML/MDS
 • Two large HCT centers either had
 insufficient power3 or saw no
 association4 with busulfan
 exposure and relapse in children
 What about with acute myeloid leukemia
 relapse?3,4 (AML) or myelodysplastic
 syndrome (MDS)
 • Similar variable target exposure
 • in children with neuroblastoma
 receiving busulfan/melphalan5
 Minimum Maximum
  engraftment  liver toxicity • in adults6
(pediatric data1) (adult data only2)
 1McCune JS, et al. J Clin Pharmacol. 2013;53(3):264-275; 2McCune JS, et al. Bone Marrow Transplant. 2002;30(3):167-173.
 3McCune JS, et al. Bone Marrow Transplant. 2002;30(3):167-173; 4Baker KS, et al. Bone Marrow Transplant. 2000;26(6):607-614.
 5ANBL12P1 unpublished data. 6McCune JS, unpublished data. 8

Variable Busulfan Target Exposure:
Clinical Intuition or Micromanaging?
• Busulfan pharmacodynamic studies are often inadequately powered single center
 studies that rarely have power analyses a priori
• To identify optimal target exposure, sought to gather data with busulfan exposure
 AND outcomes in homogenous pediatric population via Children’s Oncology
 Group (COG) ANBL12P1 and homogeneous adult population within the Blood
 and Marrow Transplant Clinical Trials Network (BMT CTN) 0901
• But….data entry of busulfan exposure very difficult to interpret because some
 × 
 centers use AUC in (mMolar×min) or concentration at steady
 
 state (Css) in (ng/ml)
 
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Not Feasible to Create Evidence-based Target Busulfan
AUC
• In 2014, the Practice Guidelines Committee of the American Society of Blood or
 Marrow Transplantation (ASBMT) sought to develop an evidence-based review
 about pharmacokinetic-guided busulfan dosing
• Committee sought to grade the relevant published studies (June 1, 2008 through
 March 31, 2016) according to criteria set forth by the Steering Committee for
 Evidence Based Reviews from ASBMT
• Published literature was too heterogeneous and lacked adequately powered
 and sufficiently controlled studies for this to be feasible
• Developed a list of most frequently asked questions (FAQs) regarding
 personalized busulfan dosing. This "Considerations" document is a list of these
 FAQs and their responses, addressing topics of practical relevance to
 hematopoietic cell transplantation clinicians

Palmer J, et al. Biol Blood Marrow Transplant. 2016;22(11):1915-1925.
 10

After ASTCT Busulfan Considerations Paper

• Goals
 —Must have busulfan exposure in a multicenter databases to create evidence-based target
 busulfan exposure
 —Minimize risk of busulfan dosing errors, as the different exposures causes confusion
• 2016: Needs assessment conducted with goal of identifying evidence gaps
 —23 busulfan labs or HCT centers invited
 —28 respondents identified 23 concerns
• 2016 – 2017: Identified 5 Steering Committee members, which prioritized 2
 projects
 —Busulfan exposure unit harmonization (BuEUH): Focus of today
 —Busulfan quantitation, modeling and dose (BuQMD): Email office@skml.nl to participate

McCune JS, et al. Biol Blood Marrow Transplant. 2019;25(9):1890-1897.
 11

Harmonization of Busulfan Plasma Exposure Unit (BPEU):
A Community-Initiated Consensus
 • Used Delphi process of
 sequential Redcap™ surveys

 • Increasingly larger circle of
 stakeholders

 • Anonymous responses

McCune JS, et al. Biol Blood Marrow Transplant. 2019;25(9):1890-1897.
 12

Harmonization of BPEU was an International
Collaboration
 3%

 13% N.America
 11% Europe
 20% 22%
 11% 24% Asia
 60%
 S.America
 22%
 80% 34% Australia

 Steering Expert Panel Task Force
 Committee (n=5) (n=9) (n=38)

McCune JS, et al. Biol Blood Marrow Transplant. 2019;25(9):1890-1897.
 13

Goal of Survey 1: Identify Properties of Ideal BPEU

• Steering Committee and Expert Panel
• Used Delphi process with sequential surveys, consensus defined a priori as
 ≥70% respondents ranking a property “moderately important” or “very important”
 on a 4-point Likert scale
• Ranked importance of the 5 properties of ideal BPEU:
 Most Important
#1: BPEU and BU dose unit relationship is clear
#2: BPEU can be expressed as total exposure
#3: BPEU used in available PK software
#4: BPEU clearly understood regardless of administration frequency
#5: BPEU avoids small decimals (

Goals of Survey 2
• Evaluate each BPEU against the properties of the ideal BPEU as established via
 Survey 1
• Evaluate each BPEU against local position statements for PK-directed busulfan
 dosing
• Identify facilitators and barriers to international harmonization to one BPEU

Survey 2 Participants
• Task Force was added to the Steering Committee and Expert Panel
• All respondents stated their willingness to harmonize to a single BPEU and 87%
 (28/32) reported that their respective institution/program would be willing to do so

McCune JS, et al. Biol Blood Marrow Transplant. 2019;25(9):1890-1897.
 15

Survey 2: Evaluate each BPEU against the Properties of
the Ideal BPEU
• Used Delphi process with sequential surveys, consensus defined a priori as
 ≥70% respondents ranking a property “moderately important” or “very important”
 on a 4-point Likert scale or ≥70% respondents “agreed” or “strongly agreed” on a
 4-point Likert scale

5 BPEU in Clinical Use µMolar x mg x h/L
 min
AUC (µMolar x min)
 #1: BPEU and BU dose unit relationship is clear 50% 92%
AUC (mg x h/L) #2: BPEU can be expressed as total exposure 89% 89%
AUC (µg x h/L) #3: BPEU used in available PK software 84% 76%

AUC (µMolar x h) #4: BPEU clearly understood regardless of 95% 68%
 administration frequency
Css (ng/mL) #5: BPEU avoids small decimals (≤0.01) 66% 63%

McCune JS, et al. Biol Blood Marrow Transplant. 2019;25(9):1890-1897.
 16

Survey 2: Evaluate each BPEU against Local Position
Statements for PK-directed Busulfan Dosing
• The Steering Committee, Expert Panel and Task Force identified only one local position
 statement Royal College of Pathologists of Australia
• Survey question was as follows: We also draw to your attention the 2010 Position
 Statement of the Royal College of Pathologists of Australia (Table 4) that states: “....It is
 recommended that mass units be used routinely for reporting results of therapeutic drug
 concentrations measured by pathology laboratories in Australia and New Zealand. It is
 also recommended that the litre (liter in American spelling, L) be used as the
 denominator when expressing the concentration. Examples of these units are mg/L and
 μg/L. These recommendations relate to drugs which are normally given therapeutically,
 whether measured for therapeutic drug monitoring purposes or assessment of
 overdose.”
 × × 
• AUC in ( ) was chosen by 87% respondents as being in agreement
 
 with the Position Statement while 13% respondents chose AUC in mMolar×min

McCune JS, et al. Biol Blood Marrow Transplant. 2019;25(9):1890-1897.
 17

Survey 2: Identify Facilitators and Barriers to One BPEU

• Asked before the harmonized BPEU was chosen so essentially everyone knew
 they may have to convert to a single BPEU
• To facilitate a single BPEU, step-by-step instructions in the following formats:
 web-based app (most preferred), PDF available, smartphone app, video tutorial
 and one-on-one personal training (least preferred)
 —Web-based app: ASTCT app
 —PDF available: Excel spreadsheet on Github
• Barriers to implementing a single BPEU
 —Lack of familiarity with chosen BPEU
 —Lack of perceived benefit of making change

McCune JS, et al. Biol Blood Marrow Transplant. 2019;25(9):1890-1897.
 18

Harmonized BPEU

 × 
 AUC in
 
 Endorsed by 10 major professional societies as the
 harmonized busulfan plasma exposure unit for
 reporting to HCT registry databases and
 for use in future protocols and publications

 19

 × 
 Endorsed by Ten Professional Societies
 
Society Representative
ACCP Hematology/ Oncology Practice and Research Network Marco Martino
ASTCT Executive Committee Miguel-Angel Perales & Navneet Majhail
ASTCT Practice Guideline Committee Paul Carpenter & Bipin Savani
BMT CTN Marcelo Pasquini & Miguel-Angel Perales
Brazil BMT Society Nelson Hamerschlak
CIBMTR Marcelo Pasquini
EBMT & EBMT Pharmacy Mohamed Mohty & Erik van Maarseveen
HOPA Susanne Liewer
IATDMCT – Chemotherapy Group Erik van Maarseveen
Korean SBMT Hyoung Jin Kang
PBMTC Michael A. Pulsipher

 McCune JS, et al. Biol Blood Marrow Transplant. 2019;25(9):1890-1897.
 20

PK-directed Busulfan Dosing by January 1, 2021

 × 
• Clinicians to provide the target busulfan AUC in
 
 × 
• Study protocols provide busulfan AUC in
 
 × 
• Laboratories to report busulfan AUC only in
 
 × 
• Data repositories collect busulfan AUC in
 
 × 
• Publications must report busulfan AUC
 
McCune JS, et al. Biol Blood Marrow Transplant. 2019;25(9):1890-1897.
 21

ARS 1: What is the harmonized unit and its date of
implementation?
 × 
A. AUC in by January 1, 2021
 
 × 
B. AUC in by January 1, 2021
 
 × 
C. AUC in by July 1, 2021
 
D. AUC in mmolar × min by January 1, 2021
 ng
E. Css in by January 1, 2021
 ml

 22

Learning Objectives

• List benefits of unit harmonization for busulfan exposure
• Convert commonly used busulfan exposure units to the harmonized unit
• Describe available tools and literature to support institutional use of the
 harmonized unit

 23

 × 
TODAY: How to Implement now to make January 1,
 
2021 Deadline

• ASTCT offers educational programs to support this implementation
• Within each individual institution:
 × 
 —Institution’s current busulfan units training for conversion to
 
 —Involve all major stakeholders: laboratory, nurses, pharmacists, physicians,
 transplant coordinators
 —Laboratory’s reported units should include both institution’s current units and
 microgram/liter
 × 
 —Laboratory information management system to include
 
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 × 
 Already Used Within Protocols
 
• There will be a time period where those protocols initiated before January 1, 2021
 will used other busulfan plasma exposure units. The resources within GitHub and
 ASTCT app are available to convert between units.
 × 
• Starting in late 2018, new protocols written using
 
 —BMT – CTN led by Miguel-Angel Perales
 —CIBMTR led by Marcelo Pasquini and Miguel-Angel Perales
 —COG led by Jeannine McCune and Michael Pulsipher
 × 
 —EBMT protocols already use
 
 —PBMTC led by Michael Pulsipher

 25

 × 
 How Do I Convert to ?
 
Busulfan. https://pubchem.ncbi.nlm.nih.gov/compound/2478. Accessed January 17, 2020.
 26

 × 
Practical Tips for AUC in
 
• Molecular weight of busulfan = 246.292 (rounded to 246.3)
 grams/mole

 × 
• Target AUC only to tenth decimals (e.g., AUC of 14.4 )
 
Busulfan. https://pubchem.ncbi.nlm.nih.gov/compound/2478. Accessed January 17, 2020.
 27

Example 1:
 
Busulfan concentration in μMolar and Need to Report in ( )
 
• 17 

 246.3 
• 17 ×
 1 

 246.3 
• 17 × = 4187
 1 

 Just multiply concentration in µmolar by 246.3
 
Remember =
 
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Example 2:
 × 
Busulfan AUC in μMolar × min and Need to Report AUC in
 
 246.3 1 1ℎ ×ℎ
• 5262 × min ×( ) × ( ) × ( ) = 21.6
 1 1000 60 

 × 246.3 1 1ℎ ×ℎ
• 5262 ( ) ×( ) ×( ) ×( ) = 21.6
 1 1000 60 

 × 246.3 1 1ℎ ×ℎ
• 5262 ( ) ×( ) ×( ) ×( ) = 21.6
 1 1000 60 

 Just multiply AUC in µmolar x min by 246.3 and
 divide by 60,000 29

Example 3: Q24H Dosing Frequency
 × 
Busulfan Css in and Need to Report AUC in
 
 1 1,000 ×ℎ
• 900 × × × 24ℎ = 21.6
 1,000,000 

 1 1,000 ×ℎ
• 900 × × × 24ℎ = 21.6
 1,000,000 

 Multiply Css by dosing frequency in hours and divide by 1,000

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ARS 2: Which busulfan plasma exposure is equivalent to
 × 
an AUC = 20 after one dose of Q24H IV busulfan?
 
 × 
A. AUC of 80 after one dose of Q6H IV busulfan
 
B. AUC of 4872 mmolar × after one dose of Q24H IV busulfan
C. AUC of 600 mmolar × after one dose of Q6H IV busulfan
 ng
D. Css in 833 , cumulative after four doses of Q24H IV busulfan
 ml
 ng
E. Css of 633 after one dose of Q24H IV busulfan
 ml

 31

Learning Objectives

• List benefits of unit harmonization for busulfan exposure
• Convert commonly used busulfan exposure units to the harmonized unit
• Describe available tools and literature to support institutional use of the
 harmonized unit

 32

Resource 1: Github Repository

• How to get there
 —https://github.com/
 —Search “busulfan pharmacokinetics”. There are many GitHub repositories regarding busulfan
 so just searching “busulfan” provides too many hits (in my humble opinion)
 —https://github.com/busulfanpk/busulfan-pharmacokinetics
• This Github repository had substantial amount of revisions and testing before
 launch. It is managed by ASTCT.
 × 
• Resources that can be downloaded to help you convert to
 
 —BusulfanPK_TechnicalAppendix_v2.docx
 • Outdated version is appendix to Palmer J and McCune JS et al. Personalizing Busulfan-Based
 Conditioning: Considerations from the American Society for Blood and Marrow Transplantation
 Practice Guidelines Committee. Biol Blood Marrow Transplant. 2016 Nov;22(11):1915-1925
 —Busulfan concentration exposure unit converter_v2.xls: Excel workbook

 33

Resource 2: ASTCT App
Desktop: http://tgapp.asbmt.org/ and iPhone App

 34

ASTCT App: Exposure Conversion

 35

ARS 3: What resources are available to support
 × 
implementation of by January 1, 2021?
 
A. Github and one-on-one tutoring
B. Github and ASTCT app
C. One-on-one tutoring and ASTCT app
D. ASTCT app and training videos
E. None

 36

Conclusions

• The busulfan plasma exposure harmonization unit project included as many as
 possible multidisciplinary and international participants
• Target AUC (in protocols and clinically used), laboratories, data repositories and
 × 
 publications must use by January 1, 2021
 
• There are many resources to convert and double-check your conversion between
 busulfan concentrations and plasma exposure

McCune JS, et al. Biol Blood Marrow Transplant. 2019;25(9):1890-1897.
 37

Questions

 38

Recommended Reading

• Palmer J, McCune JS, Perales MA, et al. Personalizing busulfan-based
 conditioning: considerations from the American Society for Blood and Marrow
 Transplantation Practice Guidelines Committee. Biol Blood Marrow Transplant
 2016;22:1915-25.
• McCune JS, Quinones CM, Ritchie J, et al. Harmonization of busulfan plasma
 exposure unit (BPEU): a community-initiated consensus statement. Biol Blood
 Marrow Transplant 2019;25(9):1890-1897.
• https://github.com/busulfanpk/busulfan-pharmacokinetics

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