1.
Allogeneic Transplantation after Myeloablative Rituximab/BEAM +/- Bortezomib for Patients with Relapsed/Refractory Lymphoid Malignancies: 5-Year Follow-up Results
Chamoun, K., Milton, D. R., Ledesma, C., Young, K. H., Jabbour, E. J., Alatrash, G., Anderlini, P., Bashir, Q., Ciurea, S. O., Marin, D., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
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Abstract
Although bortezomib and rituximab have synergistic activity in patients with lymphoma, and can both attenuate graft-versus-host disease (GVHD), the drugs have not been used together in patients undergoing allogeneic stem-cell transplantation (alloSCT). In this phase 1/2 trial, we assessed the safety and activity of bortezomib added to the rituximab (R) plus BEAM (carmustine, etoposide, cytarabine, melphalan) regimen in patients with relapsed lymphoma undergoing alloSCT. Primary GVHD prophylaxis consisted of tacrolimus and methotrexate. Bortezomib (1 - 1.3 mg/m(2) per dose) was administered intravenously on days -13, -6, -1, and +2. We performed inverse probability weighting analysis to compare GVHD and survival results to a historical control group that received R-BEAM without bortezomib. Thirty-nine patients were assessable for toxic effects and response. The median age was 54 years. The most common diagnosis was diffuse large B-cell lymphoma (41%). Twenty-two patients (56%) and 17 patients (44%) received their transplants from matched related and unrelated matched donors, respectively. The maximum tolerated bortezomib dose was 1 mg/m(2). The weighted cumulative incidences of grade II-IV and grade III or IV acute GVHD were 50% and 34%, respectively; these incidences and survival rates were not significantly different from those of the control group. Median survival has not been reached in patients age ≤50 years and who had a long follow-up time of 60.7 months. The R-BEAM regimen has a survival benefit in lymphoma patients age ≤50 years undergoing alloSCT. The addition of bortezomib has no impact on survival or incidence of GVHD.
PICO Summary
Population
Patients with relapsed lymphoma undergoing allo-SCT
Intervention
Bortezomib added to the rituximab plus BEAM (carmustine, etoposide, cytarabine, melphalan) regimen (n=39)
Comparison
Historical control group that received R-BEAM without bortezomib.
Outcome
The R-BEAM regimen has a survival benefit in lymphoma patients age </=50 years undergoing alloSCT. The addition of bortezomib has no impact on survival or incidence of GVHD.
2.
Fludarabine with pharmacokinetically guided IV busulfan is superior to fixed-dose delivery in pretransplant conditioning of AML/MDS patients
Andersson, B. S., Thall, P. F., Valdez, B. C., Milton, D. R., Al-Atrash, G., Chen, J., Gulbis, A., Chu, D., Martinez, C., Parmar, S., et al
Bone Marrow Transplantation. 2017;52(4):580-587
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Abstract
We hypothesized that IV busulfan (Bu) dosing could be safely intensified through pharmacokinetic (PK-) dose guidance to minimize the inter-patient variability in systemic exposure (SE) associated with body-sized dosing, and that this should improve outcome of AML/MDS patients undergoing allogeneic stem cell transplantation. To test this hypothesis, we treated 218 patients (median age 50.7 years, male/female 50/50%) with fludarabine 40mg/m2 once daily x4, each dose followed by IV Bu, randomized to 130mg/m2 (N=107) or PK-guided to average daily SE, AUC of 6000muMmin (N=111), stratified for remission status and allo-grafting from HLA-matched donors. Toxicity and GvHD rates in the groups were similar; the risk of relapse or treatment-related mortality remained higher in the fixed-dose group throughout the 80-month observation period. Further, PK-guidance yielded safer disease control, leading to improved overall and PFS, most prominently in MDS patients and in AML patients not in remission at allogeneic stem cell transplantation. We conclude that AML/MDS patients receiving pretransplant conditioning treatment with our 4-day regimen may benefit significantly from PK-guided Bu dosing. This could be considered an alternative to fixed-dose delivery since it provides the benefit of precise dose delivery to a predetermined SE without increasing risk(s) of serious toxicity and/or GvHD.