TY - JOUR
T1 - Intermediate-dose posttransplantation cyclophosphamide for myeloablative HLA-haploidentical bone marrow transplantation
AU - Hyder, Mustafa A.
AU - Dimitrova, Dimana
AU - Sabina, Ruby
AU - DeVries, Ashley
AU - McCune, Jeannine S.
AU - McAdams, Meredith J.
AU - Flomerfelt, Francis A.
AU - McKeown, Christi
AU - Sadler, Jennifer L.
AU - Chai, Amy
AU - Hughes, Thomas E.
AU - Napier, Scott
AU - Stokes, Anita
AU - Sponaugle, Jennifer
AU - Rechache, Kamil
AU - Parta, Mark
AU - Cuellar-Rodriguez, Jennifer
AU - Figg, William D.
AU - Choo-Wosoba, Hyoyoung
AU - Steinberg, Seth M.
AU - Kanakry, Jennifer A.
AU - Kanakry, Christopher G.
N1 - Publisher Copyright:
© 2025 American Society of Hematology. All rights reserved.
PY - 2025/5/27
Y1 - 2025/5/27
N2 - High-dose posttransplantation cyclophosphamide (HD-PTCy), given at 50 mg/kg/day on days +3/+4, is a standard-of-care graft-versus-host disease (GVHD) prophylaxis for allogeneic hematopoietic cell transplantation (HCT). Our murine MHC-haploidentical HCT studies suggested intermediate-dose PTCy produces superior GVHD control compared with HD-PTCy and PTCy is maximally effective on day +4. We conducted a single-institutional prospective phase 1/2 trial to reduce PTCy dosing to 25 mg/kg/day on days +3/+4 or on day +4 only for myeloablative HLA-haploidentical bone marrow HCT using PTCy, sirolimus, and mycophenolate mofetil. Among 35 patients, 89% were ethnic/racial minorities, 46% had high/very-high-risk disease, and median comorbidity score was 3. The phase 1 dose-limiting-toxicity, grade III-IV acute GVHD, was not observed after either reduced-PTCy dose level. PTCy 25 mg/kg/day on days +3/+4 (intermediate-dose (ID)-PTCy; n = 23), the phase 2 dose, resulted in no grade II-IV acute GVHD; 2-year cumulative incidences of chronic GVHD requiring systemic immunosuppression, nonrelapse mortality, and relapse were 13%, 17%, and 22%, and 2-year overall survival, disease-free survival, and GVHD-free/relapse-free survival were 61%, 61%, and 52%. In exploratory analysis compared with HD-PTCy (n = 5), ID-PTCy resulted in significantly faster engraftment and T-cell reconstitution, fewer transfusions, less mucositis, and reduced severity of BK-virus-associated cystitis/urethritis; area-under-the-curve exposure of 4-hydroxycyclophosphamide (4HCY), a key cyclophosphamide metabolite, correlated with these outcomes but not with chronic GVHD occurrence. Ideal-body-weight-based PTCy dosing best approximated 4HCY exposure. ID-PTCy is effective and has apparent clinical benefits compared with HD-PTCy. Before broader implementation, further studies are needed to confirm these findings and define optimal PTCy dosing across various donor/graft types. This trial was registered at www.clinicaltrials.gov as #NCT03983850.
AB - High-dose posttransplantation cyclophosphamide (HD-PTCy), given at 50 mg/kg/day on days +3/+4, is a standard-of-care graft-versus-host disease (GVHD) prophylaxis for allogeneic hematopoietic cell transplantation (HCT). Our murine MHC-haploidentical HCT studies suggested intermediate-dose PTCy produces superior GVHD control compared with HD-PTCy and PTCy is maximally effective on day +4. We conducted a single-institutional prospective phase 1/2 trial to reduce PTCy dosing to 25 mg/kg/day on days +3/+4 or on day +4 only for myeloablative HLA-haploidentical bone marrow HCT using PTCy, sirolimus, and mycophenolate mofetil. Among 35 patients, 89% were ethnic/racial minorities, 46% had high/very-high-risk disease, and median comorbidity score was 3. The phase 1 dose-limiting-toxicity, grade III-IV acute GVHD, was not observed after either reduced-PTCy dose level. PTCy 25 mg/kg/day on days +3/+4 (intermediate-dose (ID)-PTCy; n = 23), the phase 2 dose, resulted in no grade II-IV acute GVHD; 2-year cumulative incidences of chronic GVHD requiring systemic immunosuppression, nonrelapse mortality, and relapse were 13%, 17%, and 22%, and 2-year overall survival, disease-free survival, and GVHD-free/relapse-free survival were 61%, 61%, and 52%. In exploratory analysis compared with HD-PTCy (n = 5), ID-PTCy resulted in significantly faster engraftment and T-cell reconstitution, fewer transfusions, less mucositis, and reduced severity of BK-virus-associated cystitis/urethritis; area-under-the-curve exposure of 4-hydroxycyclophosphamide (4HCY), a key cyclophosphamide metabolite, correlated with these outcomes but not with chronic GVHD occurrence. Ideal-body-weight-based PTCy dosing best approximated 4HCY exposure. ID-PTCy is effective and has apparent clinical benefits compared with HD-PTCy. Before broader implementation, further studies are needed to confirm these findings and define optimal PTCy dosing across various donor/graft types. This trial was registered at www.clinicaltrials.gov as #NCT03983850.
UR - https://www.scopus.com/pages/publications/105005783576
U2 - 10.1182/bloodadvances.2024014879
DO - 10.1182/bloodadvances.2024014879
M3 - Article
C2 - 39908565
AN - SCOPUS:105005783576
SN - 2473-9529
VL - 9
SP - 2553
EP - 2569
JO - Blood Advances
JF - Blood Advances
IS - 10
ER -