1.
Myeloablative Fractionated Busulfan with Fludarabine in Older Patients: Long Term Disease-Specific Outcomes of a Prospective Phase II Clinical Trial
Mehta, R. S., Bassett, R., Chen, J., Valdez, B. C., Kawedia, J., Alousi, A. M., Anderlini, P., Al-Atrash, G., Bashir, Q., Ciurea, S. O., et al
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND Compared to reduced-intensity conditioning regimen, myeloablative conditioning (MAC) for hematopoietic stem cell transplantation (HCT) reduces relapse but is avoided in older patients due to higher non-relapse mortality (NRM). To meet the need for a myeloablative regimen for older patients, we developed a novel fludarabine and busulfan MAC regimen. We fractionated the dose of busulfan and gave it for six days over a two-week period and demonstrated the feasibility and safety of this approach. However, the disease-specific efficacy of this regimen is not known. OBJECTIVES The purpose of this study was to estimate the efficacy of fractionated busulfan regimen by estimating diseases specific survival outcomes. STUDY DESIGN The conditioning regimen consisted of busulfan and fludarabine. On days -13 and -12 before HCT, patients received 80mg/m(2) busulfan intravenously (IV) daily in an outpatient clinic. Additional chemotherapy was administered during inpatient treatment from day -6 through day -3, including fludarabine 40mg/m(2) and busulfan IV once daily. The dosing of busulfan was determined from PK analyses to achieve for the course a target AUC of 20,000±12% µmol.min, which is close to the average exposure of myeloablative dose of busulfan. 150 patients with high-risk hematological malignancies up to 75 years were enrolled on this prospective phase II study. The objective was to evaluate NRM, relapse, survival, the rates of graft-versus-host disease (GVHD), and long-term complications. RESULTS The median age of the patient population was 61 years (interquartile range, 55-67). The most common diagnoses were acute myeloid leukemia (AML; N=59, 39.3%), myelodysplastic syndrome (MDS; n=29, 19.3%), and myelofibrosis (MF; N=22, 14.7%). Most had an unrelated donor (n=93, 62%) and received peripheral blood graft (n=110, 73.3%). Over half had an HCT-Specific Comorbidity Index of =3 (n=79, 52.7%). The median follow-up among survivors was 43.4 months (IQR, 38.9-50.4). In patients with AML in complete remission, MDS, and myelofibrosis, 3 year OS was 66.7% (95% CI, 50.2-88.5%), 43.6% (95% CI, 28.6-66.4%), and 59.1% (95% CI, 41.7-83.7%) respectively. The cumulative incidence of NRM was 22% (15.3%-28.7%), extensive chronic GVHD was 27% (95% CI, 20-34%), bronchiolitis obliterans was 4.7% (95% CI, 1.3-8.1%), and secondary malignancies was 8.7% (95% CI, 4.1-13.2%) at 3 years. CONCLUSION Lengthening the duration of busulfan (fractionation) permits safe delivery of myeloablative conditioning in older patients, leading to prolonged survival.
2.
Myeloablative conditioning using timed-sequential busulfan plus fludarabine in older patients with acute myeloid leukemia: long term results of a prospective phase II clinical trial
Mehta, R. S., Bassett, R., Olson, A., Chen, J., Ahmed, S., Alousi, A. M., Anderlini, P., Al-Atrash, G., Bashir, Q., Ciurea, S. O., et al
Haematologica. 2019
3.
A randomized phase II study of standard-dose versus high-dose rituximab with BEAM in autologous stem cell transplantation for relapsed aggressive B-cell non-hodgkin lymphomas: long term results
Srour, S. A., Li, S., Popat, U. R., Qazilbash, M. H., Lozano-Cerrada, S., Maadani, F., Alousi, A., Kebriaei, P., Anderlini, P., Nieto, Y., et al
British Journal of Haematology. 2017;178(4):561-570
Abstract
High-dose rituximab (HD-R) combined with carmustine, cytarabine, etoposide and melphalan (BEAM) and autologous stem cell transplant (ASCT) was effective and tolerable in a single-arm prospective study of relapsed aggressive B-cell non-Hodgkin lymphoma (R-NHL). We performed a randomized phase 2 study comparing HD-R versus standard-dose rituximab (SD-R) in R-NHL. Ninety-three patients were randomized to HD-R (1000 mg/m2 ) (n = 42) or SD-R (375 mg/m2 ) (n = 51) administered on post-transplant days +1 and +8, using a Bayesian adaptive algorithm. The 2 treatment arms were balanced in regards to patient demographic and clinical characteristics. At a median follow-up of 7.92 years, the 5-year disease-free survival (DFS) and overall survival (OS) were 40% and 48%, respectively. We found no statistically significant differences between HD-R and SD-R in 5-year DFS (36% vs. 43%; P = 0.205) and OS (43% vs. 52%; P = 0.392). In multivariate analyses, only disease status before ASCT [residual disease versus complete remission (CR)] (hazard ratio [HR] 1.79, 95% confidence interval [CI]: 1.08-2.95) and number of prior treatments received (>2 vs. <=2 lines of treatment) (HR 1.89, 95% CI: 1.13-3.18) were associated with worse DFS and OS. Patients who had SCT while in CR or who received <=2 lines of treatment prior to SCT had better 5-year OS (57% vs. 35%; P = 0.02 and 54% vs. 30%, P = 0.001, respectively) in both arms. No differences in engraftments or adverse events were noted in the 2 arms. When combined with BEAM and ASCT in relapsed aggressive B-cell NHL, HD-R provided no DFS or OS advantage over SD-R. In patients who have been exposed to rituximab in the frontline or salvage setting, the addition of rituximab in the peri-transplant setting remains controversial.