busulfan plasma exposure unit (bpeu) harmonization...bmt ctn marcelo pasquini & miguel-angel...

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

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 20205

Bu: busulfan; Cy: cyclophosphamide; Flu: fludarabine;

TBI: total body irradiation; Mel: melphalan

Reduced IntensityConditioning (RIC)

>33% include busulfan

MyeloablativeConditioning (MAC)

>66% include busulfan

https://www.cibmtr.org/

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

1Bolinger AM, et al. Bone Marrow Transplant. 2001;28(11):1013-1018. 2Grochow LB. Semin Oncol. 1993;20(4 Suppl 4):18-25.3Radich JP, et al. Blood. 2003;102(1):31-35.

6

HCT: hematopoietic cell transplantation

VOD: veno-occlusive disease

PK-directed Busulfan Dosing

7

1

10

100

1000

10000

0 60 120 180 240 300 360 420

Busulfann (

ng/m

L)

Time (min)

• First dose based on body surface area (BSA) or body weight

• Get multiple blood samples to estimate area under the curve (AUC)

• Clearance = dose divided by AUC

• Know target AUC

• Adjust dose based on patient’s clearance to achieve target AUC

Variability in Target Exposure in Children with AML/MDS

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

What about relapse?3,4

Maximum liver toxicity

(adult data only2)

Minimum engraftment

(pediatric data1)

• Two large HCT centers either had insufficient power3 or saw no association4 with busulfan exposure and relapse in children with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)

• Similar variable target exposure• in children with neuroblastoma

receiving busulfan/melphalan5

• in adults6

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 𝐦𝐢𝐜𝐫𝐨𝐦𝐨𝐥𝐞𝐬 ×𝐦𝐢𝐧𝐮𝐭𝐞𝐬

𝐥𝐢𝐭𝐞𝐫(mMolar×min) or concentration at steady

state (Css) in 𝐧𝐚𝐧𝐨𝐠𝐫𝐚𝐦

𝐦𝐢𝐥𝐥𝐢𝐥𝐢𝐭𝐞𝐫(ng/ml)

9

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 [email protected] to participate

McCune JS, et al. Biol Blood Marrow Transplant. 2019;25(9):1890-1897.11

mailto:[email protected]

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

Harmonization of BPEU was an International Collaboration


Steering Committee (n=5)

Expert Panel(n=9)

Task Force (n=38)

60%24%

13%

3%

N.America

Europe

Asia

S.America

Australia

22%

34%22%

11%

11%

80%

20%

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:


#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 (<0.01)

Most Important

Least Important

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

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

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

AUC (µMolar x min)

AUC (mg x h/L)

AUC (µg x h/L)

AUC (µMolar x h)

Css (ng/mL)

µMolar x

min

mg x h/L

#1: BPEU and BU dose unit relationship is clear 50% 92%

#2: BPEU can be expressed as total exposure 89% 89%

#3: BPEU used in available PK software 84% 76%

#4: BPEU clearly understood regardless of

administration frequency

95% 68%

#5: BPEU avoids small decimals (≤0.01) 66% 63%

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 𝐦𝐢𝐥𝐥𝐢𝐠𝐫𝐚𝐦 ×𝐡𝐨𝐮𝐫

𝐥𝐢𝐭𝐞𝐫(𝐦𝐠 ×𝐡

𝐋) was chosen by 87% respondents as being in agreement

with the Position Statement while 13% respondents chose AUC in mMolar×min


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


AUC in 𝐦𝐠×𝐡

𝐋

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

Harmonized BPEU

𝐦𝐠×𝐡

𝐋Endorsed by Ten Professional Societies

Society RepresentativeACCP 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

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

PK-directed Busulfan Dosing by January 1, 2021

• Clinicians to provide the target busulfan AUC in 𝐦𝐠×𝐡

𝐋

• Study protocols provide busulfan AUC in 𝐦𝐠×𝐡

𝐋

• Laboratories to report busulfan AUC only in 𝐦𝐠×𝐡

𝐋

• Data repositories collect busulfan AUC in 𝐦𝐠×𝐡

𝐋

• Publications must report busulfan AUC 𝐦𝐠×𝐡

𝐋


ARS 1: What is the harmonized unit and its date of implementation?

A. AUC in 𝐦𝐠×𝐦𝐢𝐧

𝐋by January 1, 2021

B. AUC in 𝐦𝐠×𝐡


C. AUC in𝐦𝐠×𝐡

𝐋by July 1, 2021

D. AUC in mmolar × min by January 1, 2021

E. Css in ng

mlby January 1, 2021

22

Learning Objectives




23

TODAY: How to Implement 𝐦𝐠×𝐡

𝐋now 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 𝐦𝐠×𝐡

𝐋

—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 𝐦𝐠×𝐡

𝐋

24

𝐦𝐠×𝐡

𝐋Already 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 𝐦𝐠×𝐡

𝐋—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 𝐦𝐠×𝐡

𝐋

—PBMTC led by Michael Pulsipher

25

How Do I Convert to 𝐦𝐠×𝐡

𝐋?

Busulfan. https://pubchem.ncbi.nlm.nih.gov/compound/2478. Accessed January 17, 2020.26

https://pubchem.ncbi.nlm.nih.gov/compound/2478

Practical Tips for AUC in 𝐦𝐠×𝐡

𝐋

• Molecular weight of busulfan = 246.292 (rounded to 246.3) grams/mole

• Target AUC only to tenth decimals (e.g., AUC of 14.4 𝐦𝐠×𝐡

𝐋)

Busulfan. https://pubchem.ncbi.nlm.nih.gov/compound/2478. Accessed January 17, 2020.27

https://pubchem.ncbi.nlm.nih.gov/compound/2478

Example 1:

Busulfan concentration in μMolar and Need to Report in 𝜇𝑔

𝐿(𝐦𝐜𝐠

𝐋)

• 17 𝜇𝑀𝑜𝑙𝑎𝑟

• 17𝜇𝑚𝑜𝑙𝑒𝑠

𝑙𝑖𝑡𝑒𝑟×

246.3 𝜇𝑔

1 𝜇𝑚𝑜𝑙𝑒

• 17𝜇𝑚𝑜𝑙𝑒𝑠

𝑙𝑖𝑡𝑒𝑟×

246.3 𝜇𝑔

1 𝜇𝑚𝑜𝑙𝑒= 4187

𝜇𝑔

𝐿

Remember 𝜇𝑔

𝐿=

𝑛𝑔

𝑚𝐿

28

Just multiply concentration in µmolar by 246.3

Example 2:

Busulfan AUC in μMolar × min and Need to Report AUC in 𝐦𝐠×𝐡

𝐋

• 5262 𝜇𝑀𝑜𝑙𝑎𝑟 × min × (246.3 𝜇𝑔

1 𝜇𝑚𝑜𝑙𝑒) × (

1 𝑚𝑔

1000 𝜇𝑔) × (

1 ℎ

60𝑚𝑖𝑛) = 21.6

𝑚𝑔×ℎ

𝐿

• 5262 (𝜇𝑚𝑜𝑙𝑒𝑠 ×𝑚𝑖𝑛

𝑙𝑖𝑡𝑒𝑟) × (

246.3 𝜇𝑔


1𝑚𝑔

1000 𝜇𝑔) × (

1 ℎ

60𝑚𝑖𝑛) = 21.6

𝑚𝑔×ℎ

𝐿

• 5262 (𝜇𝑚𝑜𝑙𝑒𝑠 ×𝑚𝑖𝑛

𝑙𝑖𝑡𝑒𝑟) × (

246.3 𝜇𝑔


1𝑚𝑔

1000 𝜇𝑔) × (

1 ℎ

60𝑚𝑖𝑛) = 21.6

𝑚𝑔×ℎ

𝐿

29

Just multiply AUC in µmolar x min by 246.3 and

divide by 60,000

Example 3: Q24H Dosing Frequency

Busulfan Css in 𝐧𝐠

𝒎𝐋and Need to Report AUC in

𝐦𝐠×𝐡

𝐋

• 900𝑛𝑔

𝑚𝑙×

1𝑚𝑔

1,000,000 𝑛𝑔×

1,000𝑚𝑙

𝐿× 24ℎ = 21.6

𝑚𝑔×ℎ

𝐿

• 900𝑛𝑔

𝑚𝑙×

1𝑚𝑔

1,000,000 𝑛𝑔×

1,000𝑚𝑙

𝐿× 24ℎ = 21.6

𝑚𝑔×ℎ

𝐿

30

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

ARS 2: Which busulfan plasma exposure is equivalent to

an AUC = 20 𝐦𝐠×𝐡

𝐋after one dose of Q24H IV busulfan?

A. AUC of 80 𝐦𝐠×𝒉

𝐋after one dose of Q6H IV busulfan

B. AUC of 4872 mmolar × 𝑚𝑖𝑛 after one dose of Q24H IV busulfan

C. AUC of 600 mmolar × 𝑚𝑖𝑛 after one dose of Q6H IV busulfan

D. Css in 833 ng

ml, cumulative after four doses of Q24H IV busulfan

E. Css of 633 ng

mlafter one dose of Q24H IV busulfan

31

Learning Objectives




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 𝐦𝐠×𝐡

𝐋—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

https://github.com/

https://github.com/busulfanpk/busulfan-pharmacokinetics

https://www.ncbi.nlm.nih.gov/pubmed/27481448

Resource 2: ASTCT App

Desktop: http://tgapp.asbmt.org/ and iPhone App

34

http://tgapp.asbmt.org/

ASTCT App: Exposure Conversion

35

ARS 3: What resources are available to support

implementation of 𝐦𝐠×𝒎𝒊𝒏

𝐋by 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 𝐦𝐠×𝐡


• There are many resources to convert and double-check your conversion between busulfan concentrations and plasma exposure


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

39

https://github.com/busulfanpk/busulfan-pharmacokinetics

busulfan plasma exposure unit (bpeu) harmonization...bmt ctn marcelo pasquini & miguel-angel...

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