Transplantation from Matched Siblings Using Once-Daily Intravenous Busulfan/Fludarabine with Thymoglobulin: A Myeloablative Regimen with Low Nonrelapse Mortality in All But Older Patients with High-Risk Disease

Abstract

Two hundred patients received hematopoietic stem cell transplantation (HSCT) from matched sibling donors (MSD) after myeloablative conditioning including fludarabine (Flu) and once-daily intravenous busulfan (Bu). Thymoglobulin (TG) was added to methotexate (MTX) and cyclosporine (CsA) as graft-versus-host disease (GVHD) prophylaxis. For low-risk (acute leukemia CR1/CR2, CML CP1) patients projected 5-year nonrelapse mortality (NRM) and overall survival (OS) were 4% and 76% for those <or=45 years old (n = 54) and 6% and 83% for those >45 (n = 31). For high-risk (HR) patients NRM was 6% versus 27% (18% at 1 year) (P = .04) and OS 64% versus 37% (P = .47) in younger (n = 40) and older (n = 75) patients, respectively. To correct for imbalance in HR diagnoses each of 17 younger HR patients were matched with 2 older HR (OHR) patients by diagnosis and details of stage, and thereafter for other risk factors. For the younger HR and OHR patients, respectively, OS was 70% versus 37% (P = .02) and NRM 0 versus 34% (P = .02). When outcomes of OHR patients were compared with the other 3 groups combined NRM was 27% versus 5%, respectively (P = .002). Incidence of acute graft-versus-host disease (aGVHD) grade II-IV, aGVHD grade III-IV, and chronic GVHD (cGVHD) was 23% versus 10% (P = .02), 4% versus 2% (P = ns), and 66% versus 41% (P = .001), respectively. Nine of 14 nonrelapse deaths in the OHR group were related to GVHD or its treatment compared with 3 of 6 in all others (P value for GVHD related death = .01). Multivariate analysis of OS and DFS correcting for potentially confounding pretransplant factors identified only the OHR patients as having significantly increased risk (relative risk [RR] 3.32, confidence interval [CI] 1.71-6.47, P < .0001, and RR 3.32, CI 1.71-6.43, P < .0001, respectively). The effect of age on NRM is only apparent in HR patients, and is not explained by heterogeneity in diagnoses. Older HR patients experience more GVHD and more GVHD-related death than others, but NRM is no higher than reported with many nonmyeloablative regimens.

Toxic erythema of chemotherapy following i.v. BU plus fludarabine for allogeneic PBSC transplant

“…Additional studies evaluating BU were reviewed but did not report on cutaneous toxicity. 2,3,5,[7][8][9][10][11][12][13][14] Toxic erythema of chemotherapy after high-dose BU TL Parker et al development of erosions and desquamation may be the first sign of TEC; the former may be misdiagnosed as herpetic viral infections. Lastly, the duration of the cutaneous toxicity may be weeks and to date, we have found no specific therapy that alters the clinical course.…”

Zoster prophylaxis after allogeneic hematopoietic cell transplantation using acyclovir/valacyclovir followed by vaccination

“…The usual conditioning regimen during the study period was fludarabine (250 mg/m 2 ), busulfan (;12.8 mg/kg IV, pharmacokinetically adjusted), and antithymocyte globulin (Thymoglobulin; Sanofi, Paris, France; 4.5 mg/kg), 22 with or without total body irradiation (4 Gy). 23 Additional GVHD prophylaxis was provided as methotrexate (days 1, 3, 6, 11) and cyclosporine (until 3-6 months post-HCT).…”

Toxicity and efficacy of busulfan and fludarabine myeloablative conditioning for HLA-identical sibling allogeneic hematopoietic cell transplantation in AML and MDS

“…In one study, NRM after BuFlu conditioning was reduced, but older patients had more GVHD-related deaths than younger ones. 41 Retrospective comparisons of different conditioning regimens in patients with aged over 55 years suggested improved long-term outcome with BuFlu over BuCy in one study 21 while the NRM with BuFlu was similar to that reported with RIC regimens in another. 22 In this study, we evaluated the BuFlu regimen in a homogeneous series of patients with AML or MDS receiving HSCT from HLA-identical matched-sibling donors and uniform GVHD prophylaxis reducing the impact of other types of diseases and donors or prophylactic procedures.…”