TY - JOUR
T1 - Optimizing the Conditioning Regimen for Hematopoietic Cell Transplant in Myelofibrosis
T2 - Long-Term Results of a Prospective Phase II Clinical Trial
AU - Popat, Uday
AU - Mehta, Rohtesh S.
AU - Bassett, Roland
AU - Kongtim, Piyanuch
AU - Chen, Julianne
AU - Alousi, Amin M.
AU - Anderlini, Paolo
AU - Ciurea, Stefan
AU - Hosing, Chitra
AU - Jones, Roy
AU - Kebriaei, Partow
AU - Khouri, Issa
AU - Lindsay, Richard
AU - Nieto, Yago
AU - Olson, Amanda
AU - Oran, Betul
AU - Qazilbash, Muzaffar H.
AU - Rondon, Gabriela
AU - Shpall, Elizabeth J.
AU - Verstovsek, Srdan
AU - Andersson, Borje S.
AU - Champlin, Richard E.
N1 - Funding Information:
Financial disclosure:The study was supported partly by Otsuka Pharmaceutical and partly by the Cancer Center Support Grant (National Cancer Institute grant P30 CA016672, to R.B.). The grant provider had no role in the study design, data collection, data analysis, interpretation of the results, or writing of the report.
Funding Information:
The authors thank the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center (Houston, TX) for editing the manuscript. Financial disclosure:The study was supported partly by Otsuka Pharmaceutical and partly by the Cancer Center Support Grant (National Cancer Institute grant P30 CA016672, to R.B.). The grant provider had no role in the study design, data collection, data analysis, interpretation of the results, or writing of the report. Conflict of interest statement: Y.N. is a consultant for Affimed and has received research funding from Novartis, Celgene, and Astra-Zeneca. Authorship statement: U.P. conceptualized the study design, helped with interpretation of data, and ensured compliance with regulatory requirements for the clinical trial. R.S.M. contributed to interpretation of data and wrote the manuscript. R.B. contributed to data analysis and figures and wrote the statistical section of the manuscript. J.C. and G.R. helped with data collection and provided clinical data. P.K. A.M.A. P.A. S.C. C.H. R.J. P.K. I.K. R.L. Y.N. A.O. B.O. M.H.Q. E.J.S. and S.V. enrolled patients in the study and monitored clinical responses. R.E.C. and B.S.A. enrolled patients in the study and monitored clinical responses and conceptualized the study design. U.R.P. R.S.M. R.B. and J.C. had full access to the raw data. All authors approved the manuscript. The corresponding author had the final responsibility to submit for publication.
Publisher Copyright:
© 2020 American Society for Transplantation and Cellular Therapy
PY - 2020/8
Y1 - 2020/8
N2 - Optimal conditioning regimens for older patients with myelofibrosis undergoing allogeneic hematopoietic cell transplant are not known. Likewise, the role of dose intensity is not clear. We conducted a nonrandomized, prospective, phase II trial using low-dose, later escalated to high-dose (myeloablative conditioning), busulfan with fludarabine (Bu-Flu) in myelofibrosis patients up to age 74 years. The first 15 patients received i.v. busulfan 130 mg/m2/day on days –3 and –2 (“low dose”); 31 patients received high-dose conditioning, either 100 mg/m2/day (days –5 to –2; n = 4) or pharmacokinetic-guided area under the curve of 4000 μmol/min (days –5 to –2; n = 27). The primary endpoint was day 100 nonrelapse mortality (NRM). Median age was 58 years (interquartile range [IQR], 53-63). Dynamic international prognostic scoring system-plus was intermediate (n = 28) or high (n = 18). Donors were related (n = 19) or unrelated (n = 27). Cumulative incidence of NRM was 9.7% (95% confidence interval [CI], 0-20.3) at day 100 and at 3 years in the high-dose group and 0% in the low-dose group at day 100, which increased to 20% (95% CI, 0-41.9) at 3 years. With a median follow-up of 5.1 years (IQR, 3.8-6), 3-year relapse was 32.3% (95% CI, 15.4-49.1) in high dose versus 53.3% (95% CI, 26.6-80.1) in low dose. Event-free survival was 58% (95% CI, 43-78) versus 27% (95% CI, 12-62), and overall survival was 74% (95% CI, 60-91) versus 60% (95% CI, 40-91). In multivariate analysis, high-dose busulfan had a trend toward lower relapse (hazard ratio,.44; 95% CI,.18-1.07; P =.07), with no impact on NRM. Intensifying the Bu-Flu regimen using pharmacokinetic-monitoring appears to be promising in reducing relapse without increasing NRM.
AB - Optimal conditioning regimens for older patients with myelofibrosis undergoing allogeneic hematopoietic cell transplant are not known. Likewise, the role of dose intensity is not clear. We conducted a nonrandomized, prospective, phase II trial using low-dose, later escalated to high-dose (myeloablative conditioning), busulfan with fludarabine (Bu-Flu) in myelofibrosis patients up to age 74 years. The first 15 patients received i.v. busulfan 130 mg/m2/day on days –3 and –2 (“low dose”); 31 patients received high-dose conditioning, either 100 mg/m2/day (days –5 to –2; n = 4) or pharmacokinetic-guided area under the curve of 4000 μmol/min (days –5 to –2; n = 27). The primary endpoint was day 100 nonrelapse mortality (NRM). Median age was 58 years (interquartile range [IQR], 53-63). Dynamic international prognostic scoring system-plus was intermediate (n = 28) or high (n = 18). Donors were related (n = 19) or unrelated (n = 27). Cumulative incidence of NRM was 9.7% (95% confidence interval [CI], 0-20.3) at day 100 and at 3 years in the high-dose group and 0% in the low-dose group at day 100, which increased to 20% (95% CI, 0-41.9) at 3 years. With a median follow-up of 5.1 years (IQR, 3.8-6), 3-year relapse was 32.3% (95% CI, 15.4-49.1) in high dose versus 53.3% (95% CI, 26.6-80.1) in low dose. Event-free survival was 58% (95% CI, 43-78) versus 27% (95% CI, 12-62), and overall survival was 74% (95% CI, 60-91) versus 60% (95% CI, 40-91). In multivariate analysis, high-dose busulfan had a trend toward lower relapse (hazard ratio,.44; 95% CI,.18-1.07; P =.07), with no impact on NRM. Intensifying the Bu-Flu regimen using pharmacokinetic-monitoring appears to be promising in reducing relapse without increasing NRM.
KW - Myelofibrosis
KW - myeloablative
KW - reduced intensity
KW - stem cell transplant
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U2 - 10.1016/j.bbmt.2020.03.020
DO - 10.1016/j.bbmt.2020.03.020
M3 - Article
C2 - 32438043
AN - SCOPUS:85086565926
SN - 1083-8791
VL - 26
SP - 1439
EP - 1445
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
IS - 8
ER -