Intermediate-dose posttransplantation cyclophosphamide for myeloablative HLA-haploidentical bone marrow transplantation
Mustafa A. Hyder, Dimana Dimitrova, Ruby Sabina, Ashley DeVries, Jeannine S. McCune, Meredith J. McAdams, Francis A. Flomerfelt, Christi McKeown, Jennifer L. Sadler, Amy Chai, Thomas E. Hughes, Scott Napier, Anita Stokes, Jennifer Sponaugle, Kamil Rechache, Mark Parta, Jennifer Cuellar‐Rodríguez, William D. Figg, Hyoyoung Choo‐Wosoba, Seth M. Steinberg, Jennifer A. Kanakry, Christopher G. Kanakry
Abstract
ABSTRACT: 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.