Hematopoietic stem cell transplantation in children and young adults with secondary myelodysplastic syndrome and acute myelogenous leukemia after aplastic anemia.
Secondary myelodysplastic syndrome and acute myelogenous leukemia (sMDS/sAML) are the most serious secondary events occurring after immunosuppressive therapy in patients with aplastic anemia. Here we evaluate the outcome of hematopoietic stem cell transplantation (HSCT) in 17 children and young adults with sMDS/sAML after childhood aplastic anemia. The median interval between the diagnosis of aplastic anemia and the development of sMDS/sAML was 2.9 years (range, 1.2 to 13.0 years). At a median age of 13.1 years (range, 4.4 to 26.7 years), patients underwent HSCT with bone marrow (n = 6) or peripheral blood stem cell (n = 11) grafts from HLA-matched sibling donors (n = 2), mismatched family donors (n = 2), or unrelated donors (n = 13). Monosomy 7 was detected in 13 patients. The preparative regimen consisted of busulfan, cyclophosphamide, and melphalan in 11 patients and other agents in 6 patients. All patients achieved neutrophil engraftment. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 47%, and that of chronic GVHD was 70%. Relapse occurred in 1 patient. The major cause of death was transplant-related complication (n = 9). Overall survival and event-free survival at 5 years after HSCT were both 41%. In summary, this study indicates that HSCT is a curative therapy for some patients with sMDS/sAML after aplastic anemia. Future efforts should focus on reducing transplantation-related mortality.
Yoshimi A
，Strahm B
，Baumann I
，Furlan I
，Schwarz S
，Teigler-Schlegel A
，Walther JU
，Schlegelberger B
，Göhring G
，Nöllke P
，Führer M
，Niemeyer CM
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Busulfan dose intensity and outcomes in reduced-intensity allogeneic peripheral blood stem cell transplantation for myelodysplastic syndrome or acute myeloid leukemia.
Comparisons of myeloablative conditioning versus reduced-intensity conditioning (RIC) have demonstrated a tradeoff between relapse and toxicity. Dose intensity across RIC regimens vary and may affect treatment outcomes. In this retrospective analysis, we investigated the effect of i.v. busulfan dosing (total dose 3.2 mg/kg versus 6.4 mg/kg) in RIC regimens that combined fludarabine and busulfan on outcomes in patients who were undergoing hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). A total of 217 consecutive patients with MDS or AML underwent first busulfan and fludarabine RIC peripheral blood stem cell transplantation from well-matched related or unrelated donors at our institutions between 2004 and 2009. Of the 217 patients, 135 patients received Bu1 (3.2 mg/kg of busulfan) and 82 patients received Bu2 (6.4 mg/kg of busulfan), both with daily fludarabine (30 mg/m(2)/day for 4 days). The choice of RIC regimen was based on temporal institutional standard, enrollment on protocols, and physician choice. Patients had similar characteristics with a few notable differences: Patients who received Bu1 were younger (median age 61 versus 64 years, P < . 001), received more single-antigen mismatched unrelated grafts (14.1% versus 1.2%, P < . 001), received more sirolimus-based graft-versus-host disease (GVHD) prophylaxis regimens (63% versus 45%, P < .0001), received less antithymocyte globulin for GVHD prophylaxis (0% versus 22%, P < .001), and had less enrollment on a clinical trial that used prophylactic rituximab for the prevention of chronic GVHD (2.2% versus 11.0%, P = .011). Clinical disease status was similar between the groups. Median follow-up for survivors was 4.4 years for Bu1 and 3.2 years for Bu2. Because of the differences in characteristics, the 2 groups were compared with the adjustment of a propensity score that predicted Bu2 to account for measured differences. The day +200 cumulative incidence rates of grades II to IV acute GVHD (Bu1, 17%, versus Bu2, 8.5%; hazard ratio [HR], .56; 95% confidence interval [CI], .22 to 1.41; P = .22) or grades III to IV acute GVHD (Bu1, 6.7%, versus Bu2, 4.9%) were not different. The 2-year cumulative incidence of chronic GVHD was not significantly different between Bu1 and Bu2 (41.5% versus 28%, respectively; HR, .70; CI, .42 to 1.17; P = .09). Two-year nonrelapse mortality rates were similar for Bu1 and Bu2 (8.9% versus 9.8%, respectively; HR, .80; CI, .29 to 2.21; P = .67). Two-year progression-free survival and overall survival were also similar between Bu1 and Bu2 (progression-free survival: 40.6% versus 39.3%, respectively; HR, .82; CI, .57 to 1.30; P = .33; and overall survival: 47.4% versus 48.8%, respectively; HR, .96; CI, .64 to 1.44; P = .85). Subset analysis defined by clinical disease and cytogenetic risk with the propensity risk score applied suggest that in patients with high clinical disease risk and nonadverse cytogenetics, the higher dose busulfan RIC regimen may be of marginal benefit (2-year progression-free survival: HR, .54; CI, .29 to 1.03; P = .062). For the majority of patients with MDS or AML undergoing busulfan and fludarabine RIC peripheral blood stem cell transplantation, however, the dose of busulfan (3.2 mg/kg versus 6.4 mg/kg) is not associated with significant differences in overall outcomes.
Chen YB
，Coughlin E
，Kennedy KF
，Alyea EP
，Armand P
，Attar EC
，Ballen KK
，Cutler C
，Dey BR
，Koreth J
，McAfee SL
，Spitzer TR
，Antin JH
，Soiffer RJ
，Ho VT
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Beneficial Role of Low-Dose Antithymocyte Globulin in Unrelated Stem Cell Transplantation for Adult Patients with Acquired Severe Aplastic Anemia: Reduction of Graft-versus-Host Disease and Improvement of Graft-versus-Host Disease-Free, Failure-Free Survi
Stem cell transplantation (SCT) from an unrelated donor (URD) is often considered in patients with severe aplastic anemia (SAA) whom immunosuppressive therapy failed and matched sibling donor is not available. To reduce the incidence of graft-versus-host disease (GVHD) in URD SCT, introducting antithymocyte globulin (ATG) into the conditioning regimen has been proposed. Although ATG was shown to play a role in reducing GVHD in a cohort with diverse hematologic diseases, its role in SAA remains uncertain. The aim of this study was to determine the efficacy and toxicity of ATG in URD SCT for adult patients with SAA. We investigated 83 adult patients with SAA who underwent URD SCT between 2003 and 2014. The transplantation strategy consisted of total body irradiation (total 800 cGy) and cyclophosphamide (total 100 mg/kg to 120 mg/kg), followed by tacrolimus and a short-term methotrexate. We divided patients into 2 groups: group 1 (n = 25), which received HLA-matched (8/8) bone marrow (BM) without ATG, and group 2 (n = 58), which received SCT from either an HLA-mismatched donor or peripheral blood (PB). Thereafter, group 2 was subdivided according to ATG use into group 2A (without ATG, n = 26), which served as a historical cohort, and group 2B (with ATG, n = 32). Rabbit ATG (Thymoglobulin; Genzyme-Sanofi, Lyon, France) was used in group 2B at a dose of 2.5 mg/kg. The median age of all patients was 30 years (range, 17 to 59 years). The incidence of GVHD was significantly lower in group 2B than group 2A, as demonstrated by the rate of grade II to IV acute GVHD at day 100 (31.2% versus 61.5%, P = .003) and the rate of chronic GVHD at 3 years (21.9% versus 65.4%, P = .002). The overall survival rates of the 3 groups were similar. However, GVHD-free, failure-free survival (GFFS) was significantly higher in group 2B than group 2A (P = .034). A multivariable model identified use of ATG as an independent factor affecting grades II to IV acute GVHD (hazard ratio [HR], 2.902; 95% confidence interval [CI], 1.417 to 5.942; P = .004), chronic GVHD (HR , 3.005; 95% CI, 1.279 to 7.059; P = .012), and GFFS (HR, 2.363; 95% CI, 1.162 to 4.805; P = .014). Toxicities, including infectious complications, were not different among the 3 groups. In conclusion, low-dose ATG (2.5 mg/kg) can reduce the incidence of acute and chronic GVHD and improve the quality of life in patients with SAA who receive stem cells from either an HLA-mismatched donor or PB; importantly, these benefits are achieved without increased toxicity. Furthermore, ATG can be considered in URD SCT from HLA-matched BM cells.
Park SS
，Kwak DH
，Jeon YW
，Yoon JH
，Lee SE
，Cho BS
，Eom KS
，Kim YJ
，Kim HJ
，Lee S
，Min CK
，Cho SG
，Kim DW
，Min WS
，Lee JW
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