Letter to the Editor Regarding “Harmonization of Busulfan Plasma Exposure Unit (BPEU): A Community-Initiated Consensus Statement”
Year: 2020
Type: letter
Abstract: We read with great interest the recent article by McCune et al [1McCune J.S. Quinones C.M. Ritchie J. et al.Harmonization of Busulfan Plasma Exposure Unit (BPEU): A community-initiated consensus statement.Biol Blood Marrow Transplant. 2019; 25: 1890-1897https://doi.org/10.1016/j.bbmt.2019.05.021Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar] and commend the authors for undertaking the huge task of asking hematopoietic cell transplantation (HCT) experts and practitioners from across the globe to reach a consensus and harmonize the busulfan plasma exposure unit (BPEU). Harmonization of the BPEU will help facilitate busulfan pharmacokinetic (PK) data capture by HCT registry databases and prevent potential misinterpretation of publications and protocols. The authors used a rigorous Delphi method to achieve this objective; however, the Task Force did not achieve the consensus threshold for the BPEU chosen by the study's Steering Committee. Here we outline our concerns about what we perceive as flaws in this study and its conclusions, and explain why the authors should consider reaching out again to the HCT community to include more transplantation centers and choose a BPEU that meets the consensus threshold initially proposed in this study. The Steering Committee and Expert Panel defined consensus a priori as ≥70% agreement among the respondents. This is a good consensus definition because it removes ambiguity and makes the statement unequivocal and easy to implement. The Steering Committee followed this consensus statement through all rounds of the surveys, except for the final round. The area under the curve (AUC) in µM × min, was identified as the most commonly used BPEU by >50% of responders in surveys 1 and 2 (rounds 1 to 4). In the fifth and final round of survey 2, participants were asked whether AUC in mg × h/L is an appropriate BPEU for international harmonization. The task force was evenly split, with 17 members (50%) disagreeing or strongly disagreeing with the proposed new BPEU and 17 (50%) agreeing or strongly agreeing with this new BPEU. Another survey round or opening up the surveys to more community members would have been an ideal next step. Instead, however, the Steering Committee made the decision to use AUC mg × h/L as the harmonized BPEU, believing that it best aligns with the aggregate of survey responses. This is a nonsequitur to an otherwise well-designed study. We believe that this deviation from the initial study design dismisses the judgment of the numerous stakeholders in the HCT community invited to participate in the surveys, as well as the opinions of those not invited to participate. Finally, it ignores the fact that mg × h/L is currently used only by a minority of centers reporting to international transplant registries. The total number of survey participants, including the Steering Committee, Expert Panel, and Task Force, was only 52. Of these, 39 (75%) participated in round 1 of survey 2, with participation decreasing for subsequent rounds of the survey. These low numbers may be secondary to the recruitment of Task Force members via personal or professional networks. This community initiative could have had greater input had all stakeholders or representatives from all transplantation centers had been invited to participate in the surveys. According to the Center for International Blood & Marrow Transplant Research (CIBMTR), as of February 26, 2018, there were 180 US transplantation centers performing allogeneic related donor HCT, 163 centers performing allogeneic unrelated donor HCT, and 188 centers performing autologous HCT. Other recent surveys have included larger numbers of participants. One such survey, conducted in 2015 by Majhail et al [2Majhail N.S. Mau L.W. Chitphakdithai P. et al.National survey of hematopoietic cell transplantation center personnel, infrastructure, and models of care delivery.Biol Blood Marrow Transplant. 2015; 21: 1308-1314Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar], included 172 transplantation centers. Preliminary data obtained from the CIBMTR indicated that 184 (88%) US transplantation centers and 150 (88%) international transplantation centers used busulfan-based conditioning regimens in 2011 to 2015 [2Majhail N.S. Mau L.W. Chitphakdithai P. et al.National survey of hematopoietic cell transplantation center personnel, infrastructure, and models of care delivery.Biol Blood Marrow Transplant. 2015; 21: 1308-1314Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar], the most recent time period for which data are available. Although we do not know the total number of transplantation centers worldwide, we can safely estimate that the Steering Committee would have received more valid input with a significantly greater impact had representatives from a larger number of transplantation centers been included in the Task Force. This statement was written to ensure that pathology laboratories would report the plasma concentrations in mass units per liter (ie, mg/L, µg/L, or ng/L). The rationale for this was an easy conversion of plasma concentration to dosage for therapeutic drug monitoring based on the linear relationship between drug concentration and dose or adjustments based on trough concentrations, as used for such drugs as tacrolimus, vancomycin, β-lactams, adalimumab, infliximab, and aztreonam [3Assa A. Matar M. 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The position statement acknowledges the limitation of this approach when the PK are not linear and more complex or thorough PK analyses are needed. In addition, the statement allows the reporting of concentration in molar units if there is uniformity of reporting and a consensus for the use of those units, for example, for methotrexate (µmol/L). Based on this allowance, we believe that achieving uniformity is more likely with the BPEU of AUC in µM × min, because >50% of survey responders reported using this BPEU compared with the 16% to 23% of the responders in survey 2 using a BPEU of AUC in mg × h/L. Therefore, we are in agreement with the 33% (12 of 36) of survey 2, round 2 respondents who considered an AUC in µM × min the BPEU in closest agreement with the Royal College of Pathologists of Australia 2010 Position Statement. The Steering Committee further promotes the use of mg × h/L because it allows for easy calculation of busulfan dose based on exposure and preclues an extra step of conversion of mg to molar. The calculation of a new dose based on total exposure (survey 1, round 2) is more complicated. For a test dose busulfan PK, the dose can be calculated based on the total exposure divided by the number of days of busulfan administration. It becomes a multistep process if the busulfan PK is performed during therapeutic exposure, comprising the following steps. First, based on busulfan clearance, calculate the exposure up to the last busulfan dose before dose adjustment; then calculate the new exposure to achieve the total exposure; and finally calculate the new dose based on busulfan clearance. It is clear that the AUC in mg × h/L will not make busulfan dose calculation a straightforward process. Use of AUC mg × h/L versus AUC µM × min as the Single BPEU According to this study, >50% of the HCT community uses the BPEU of AUC µM × min, which adheres to the SI system (International System of Units). An argument can be made that it is appropriate to harmonize uniform BPEU reporting with the SI system and its revised units that took effect this year, potentially avoiding the use of a BPEU that may need to be revised again within the next 2 to 5 years. McCune et al report that the new BPEU has already received support from 10 professional societies. The authors are also representatives of 9 of the 11 professional societies mentioned in their Table 5. In addition, 6 of those professional societies were represented on the Steering Committee or Expert Panels. Given the potential for bias, we believe that these affiliations should have been more clearly acknowledged by the authors. The authors have developed an aggressive timeline for implementing AUC in mg × h/L by January 1, 2021 (19 months from the publication of their article). Doing this will require significant changes in practice for many transplantation centers, beginning with the updating of order sets and/or treatment plans; for example, the University of Texas MD Anderson Cancer Center has approximately 150 active stem cell transplantation treatment plans. A significant number of clinical pharmacist hours are required to update and validate changes to orders, order sets, and treatment plans. The transition to a new BPEU will come with an increased risk of medical and dosing errors that could cause significant harm to patients. Given that approximately 98,000 people in the United States die each year from medical errors that occur in hospitals, great care must be taken when transitioning to a new BPEU [9Institute of Medicine Committee on Quality of Health Care in AmericaKohn L.T. Corrigan J.M. Donaldson M.S. To Err is Human: Building a Safer Health System. WashingtonNational Academies Press, DC2000Google Scholar]. The authors also recommend using AUC in mg × h/L in future publications. Because many institutions have ongoing clinical studies, changing current protocols or publishing with the new BPEU while an institution is still using a different BPEU in practice is an undue burden that increases the potential for errors. We believe that the transition to publishing the BPEU of AUC in mg × h/L should occur after the successful implementation of the new BPEU and then only in newly initiated clinical studies. In summary, the Steering Committee has undertaken the difficult task of harmonizing the BPEU; however, the prespecified consensus threshold was not reached, and a consensus decision was not made. The BPEU decision making process would have been strengthened by including more members of the HCT community on the Task Force. Given the amount of work needed to safely and successfully transition to the new BPEU, the aggressive timeline for implementation should be reconsidered, to decrease the risk of serious medication errors. This difficulty is further enhanced because >50% of transplantation centers use the BPEU of AUC in µM × min, which already adheres to the SI system. Based on these concerns, we request that the authors and the ASTCT consider reopening these surveys to include a larger number of transplantation centers, to determine a consensus BPEU endorsed by ≥70% of participants and professional societies. The data presented here are preliminary and were obtained from the Coordinating Center of the Center for International Blood and Marrow Transplant Research. The analysis has not been reviewed or approved by the Advisory or Scientific Committee of the CIBMTR.
Institution: The University of Texas MD Anderson Cancer Center
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W3023793552