TY - JOUR
T1 - A Phase II Multicenter Study of the Addition of Azacitidine to Reduced-Intensity Conditioning Allogeneic Transplant for High-Risk Myelodysplasia (and Older Patients with Acute Myeloid Leukemia)
T2 - Results of CALGB 100801 (Alliance)
AU - Vij, Ravi
AU - Le-Rademacher, Jennifer
AU - Laumann, Kristina
AU - Hars, Vera
AU - Owzar, Kouros
AU - Shore, Tsiporah
AU - Vasu, Sumithira
AU - Cashen, Amanda
AU - Isola, Luis
AU - Shea, Thomas
AU - DeMagalhaes-Silverman, Margarida
AU - Hurd, David
AU - Meehan, Kenneth
AU - Beardell, Frank
AU - Devine, Steven
N1 - Funding Information:
Financial disclosure: Supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology ) and U10CA180833 , U10CA180838 , U10CA180850 , U10CA180854 , and UG1CA189819 . Also supported in part by funds from Otsuka. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
The following institutional networks participated in this study: Dartmouth College, Norris Cotton Cancer Center Lead Academic Participating Sites (LAPS), Lebanon, NH, Konstantin Dragnev, U10CA180854; Delaware/Christiana Care NCI Community Oncology Research Program, Newark, DE, Gregory Masters, UG1CA189819; Mount Sinai Hospital, New York, NY, Lewis Silverman; The Ohio State University Comprehensive Cancer CenterLAPS, Columbus, OH, Claire Verschraegen, U10CA180850; UNC Lineberger Comprehensive Cancer Center LAPS, Chapel Hill, NC, Thomas Shea, U10CA180838; University of Iowa/Holden Comprehensive Cancer Center, Iowa City, IA, Umar Farooq; University of Maryland/Greenebaum Cancer Center, Baltimore, MD, Heather Mannuel; Wake Forest University Health Sciences, Winston-Salem, NC, Heidi Klepin; Washington University, Siteman Cancer Center LAPS, Saint Louis, MO, Nancy Bartlett, U10CA180833; and Weill Medical College of Cornell University, New York, NY, Scott Tagawa. Financial disclosure: Supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology) and U10CA180833, U10CA180838, U10CA180850, U10CA180854, and UG1CA189819. Also supported in part by funds from Otsuka. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Conflict of interest statement: There are no conflicts of interest to report.
Publisher Copyright:
© 2019 American Society for Transplantation and Cellular Therapy
PY - 2019/10
Y1 - 2019/10
N2 - Relapse remains the major cause of death in older patients transplanted for acute myeloid leukemia (AML) in first complete remission or for patients with advanced myelodysplastic syndrome (MDS) at any age. Conventional myeloablative conditioning followed by allogeneic blood or marrow transplantation is associated with significantly less relapse compared with reduced-intensity conditioning when performed in younger patients with AML or MDS, but the toxicity of this approach in older patients is prohibitive. We hypothesized that pharmacokinetic targeting to optimize busulfan (BU) exposure, combined with the administration of azacitidine (AZA) post-transplant would mitigate the risk of relapse while reducing nonrelapse mortality and ultimately improve progression-free survival (PFS). On this phase II multicenter study, 63 patients (40 unrelated donors and 23 matched related donors) received a uniform conditioning regimen consisting of fludarabine i.v. (days –7 to –3), BU targeted to a daily area under the curve (AUC) of 4000 μM/min (days –6 to –3) after the administration of a 25-mg/m2 i.v. test dose on 1 day between days –14 to –9, and antithymocyte globulin (days –6, –5, and –4 (2 doses for matched related donors and 3 for matched unrelated donors only). Beginning on days +42 to +90, all patients were planned to receive up to 6 monthly cycles of AZA at 32 mg/m2 subcutaneously for 5 days. The median age was 62 years (range, 44 to 74); 13 had AML and 50 had MDS; 87% of patients were within 20% of the target AUC based on a validation sample. Forty-one patients (65%) started AZA at a median of 61 days (range, 43 to 91) post-transplant, and 17 patients (41%) completed all 6 cycles of AZA. The cumulative incidence of nonrelapse mortality at 2 years was 33.4% (95% confidence interval [CI], 22%-45%). The cumulative incidence of relapse was 25% (95% CI, 15%-37%) at 2 years. With a median follow-up of 58.9 months, the estimated PFS probability at 2 years and 5 years after transplantation was 41.2% (80% CI, 33.9%-49.9%) and 26.9% (80% CI, 20.4%-35.5%), respectively, for the entire group with a median PFS of 15.8 months (95% CI, 6.7 to 28.3). The probability of overall survival at 2 and 5 years was 45.7% (95% CI, 34.9%-59.9%) and 31.2% (95% CI, 21.3% to 45.8%), respectively, for the entire group with a median overall survival of 19.2 months (95% CI, 8.7 to 37.5). In summary, we demonstrated the feasibility of a novel reduced-intensity conditioning regimen with test dose BU targeted to an AUC of 4000 μM/min. The feasibility of AZA in this setting appears to be limited if applied to an unselected population of older hematopoietic stem cell transplantation recipients. (ClinicalTrials.gov Identifier: NCT01168219.)
AB - Relapse remains the major cause of death in older patients transplanted for acute myeloid leukemia (AML) in first complete remission or for patients with advanced myelodysplastic syndrome (MDS) at any age. Conventional myeloablative conditioning followed by allogeneic blood or marrow transplantation is associated with significantly less relapse compared with reduced-intensity conditioning when performed in younger patients with AML or MDS, but the toxicity of this approach in older patients is prohibitive. We hypothesized that pharmacokinetic targeting to optimize busulfan (BU) exposure, combined with the administration of azacitidine (AZA) post-transplant would mitigate the risk of relapse while reducing nonrelapse mortality and ultimately improve progression-free survival (PFS). On this phase II multicenter study, 63 patients (40 unrelated donors and 23 matched related donors) received a uniform conditioning regimen consisting of fludarabine i.v. (days –7 to –3), BU targeted to a daily area under the curve (AUC) of 4000 μM/min (days –6 to –3) after the administration of a 25-mg/m2 i.v. test dose on 1 day between days –14 to –9, and antithymocyte globulin (days –6, –5, and –4 (2 doses for matched related donors and 3 for matched unrelated donors only). Beginning on days +42 to +90, all patients were planned to receive up to 6 monthly cycles of AZA at 32 mg/m2 subcutaneously for 5 days. The median age was 62 years (range, 44 to 74); 13 had AML and 50 had MDS; 87% of patients were within 20% of the target AUC based on a validation sample. Forty-one patients (65%) started AZA at a median of 61 days (range, 43 to 91) post-transplant, and 17 patients (41%) completed all 6 cycles of AZA. The cumulative incidence of nonrelapse mortality at 2 years was 33.4% (95% confidence interval [CI], 22%-45%). The cumulative incidence of relapse was 25% (95% CI, 15%-37%) at 2 years. With a median follow-up of 58.9 months, the estimated PFS probability at 2 years and 5 years after transplantation was 41.2% (80% CI, 33.9%-49.9%) and 26.9% (80% CI, 20.4%-35.5%), respectively, for the entire group with a median PFS of 15.8 months (95% CI, 6.7 to 28.3). The probability of overall survival at 2 and 5 years was 45.7% (95% CI, 34.9%-59.9%) and 31.2% (95% CI, 21.3% to 45.8%), respectively, for the entire group with a median overall survival of 19.2 months (95% CI, 8.7 to 37.5). In summary, we demonstrated the feasibility of a novel reduced-intensity conditioning regimen with test dose BU targeted to an AUC of 4000 μM/min. The feasibility of AZA in this setting appears to be limited if applied to an unselected population of older hematopoietic stem cell transplantation recipients. (ClinicalTrials.gov Identifier: NCT01168219.)
KW - AML
KW - Azacitidine
KW - Busulfan
KW - MDS
KW - Reduced-intensity conditioning
UR - http://www.scopus.com/inward/record.url?scp=85068935698&partnerID=8YFLogxK
U2 - 10.1016/j.bbmt.2019.06.007
DO - 10.1016/j.bbmt.2019.06.007
M3 - Article
C2 - 31212080
AN - SCOPUS:85068935698
SN - 1083-8791
VL - 25
SP - 1984
EP - 1992
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
IS - 10
ER -