Significant impact of antibiotic exposure on GI-GVHD, NRM, and GRFS following allogeneic HCT with non-myeloablative Flu-TBI conditioning.

BACKGROUND: Acute gastro-intestinal graft-versus-host disease (GI-GVHD) and non-relapse mortality (NRM) after allogeneic HCT are closely related to loss of microbial diversity and intestinal dominance by single taxa resulting from the use of antibiotics, dietary changes, and mucosal barrier injury. There is a paucity of data on the impact of use of antibiotics in HCT after Flu-TBI-based non-myeloablative (NMA) conditioning where there is absence of mucositis and limited malnutrition. METHODS: We did a retrospective single-center analysis of patients receiving Flu-TBI-based NMA HCT for a high-grade myeloid malignancy, mostly AML, and MDS, or acute lymphoblastic leukemia (ALL). We analyzed the impact of pre-engraftment antibiotic exposure, prophylactic ciprofloxacin, and or treatment with broad-spectrum cephalosporin/carbapenem, on HCT outcomes, with a focus on the incidence of acute GI-GVHD by day 180 and NRM at 1 year. RESULTS: A total of 150 patients were evaluable with a median age of 62 years. Antibiotics were used in 90 patients; 60 prophylactic use only and 30 therapeutic use with or without previous prophylaxis. Antibiotic use resulted in a significant higher incidence of GI-GVHD Stage 1-4; 29% (26/90) versus 5% (3/60) in those not receiving antibiotics (OR 8.1 (95% CI 2.3-28.3), p = 0.001). Use of antibiotics resulted in higher 1-year NRM (19% (17/90) versus 10% (6/60), HR 2.3, p = 0.06), and decreased 2-year GRFS (42% (38/90) versus 55% (33/60), HR 1.7, p = 0.04), but did not impact RFS or OS. CONCLUSIONS: Use of antibiotics was related to the occurrence of GI-GVHD, NRM, and GRFS in patients receiving truly NMA HCT. Therefore, in the absence of mucositis and low incidence of bacteremia, antibiotics can and should be used restrictively in this setting.

Cyclosporine A trough concentrations are associated with acute GvHD after non-myeloablative allogeneic hematopoietic cell transplantation.

Low plasma CsA concentrations (<300-350 ng/mL) early following allogeneic hematopoietic stem cell transplantation (HSCT) is associated with an increased risk of developing acute graft-versus-host disease (aGvHD). Nevertheless, the current optimal target trough concentration for CsA following HSCT is considered to be 200-400 ng/mL. Here, we performed a retrospective analysis of a homogeneous group of 129 patients who received HSCT after non-myeloablative conditioning, and we analyzed the impact of CsA trough concentration measured during the first four weeks (CsA W1-4) on the incidence aGvHD, relapse-free survival (RFS), non-relapse mortality (NRM), overall survival (OS), and toxicity. The 180-day incidence of grade II-IV aGvHD was 25% (32/129 patients). In multivariate analysis the incidence of grade II-IV aGvHD was significantly lower among patients with a CsA W1-4 concentration ≥350 ng/mL compared to patients with a concentration <350 ng/mL (18% versus 38%, respectively; P = 0.007), with a hazard ration (HR) of 0.38 (95% CI: 0.19-0.77). In contrast, we found no correlation between CsA trough concentration and RFS, NRM, or OS. Moreover, we found an increased incidence of hypomagnesemia at higher CsA concentrations, but no difference in the incidence of acute renal toxicity, hepatic toxicity, or electrolyte imbalance. Interestingly, 30% of patients experienced hyponatremia with no apparent cause other than the use of CsA, with urinalysis suggesting SIADH as the underlying cause. Our findings suggest that a CsA trough concentration of 350-500 ng/mL might be more appropriate in the first month following non-myeloablative HSCT.

Addition of 10-Day Decitabine to Fludarabine/Total Body Irradiation Conditioning is Feasible and Induces Tumor-Associated Antigen-Specific T Cell Responses.

Allogeneic hematopoietic cell transplantation (HCT) offers the possibility of curative therapy for patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myelogenous leukemia (AML). However, post-HCT relapse remains a major problem, particularly in patients with high-risk cytogenetics and in patients who cannot tolerate consolidation chemotherapy (eg, due to previous toxicity). We assessed the toxicity and efficacy of 10-day decitabine (Dec), fludarabine (Flu), and 2 Gy total body irradiation (TBI) as a new conditioning regimen for allogeneic HCT in patients with MDS, CMML, or AML. Thirty patients were enrolled, including 11 with MDS, 2 with CMML, and 17 with AML. Patients received 20 mg/m(2)/day Dec on days -11 to -2, 30 mg/m(2)/day Flu on days -4 to -2, and 2 Gy TBI on day -1, followed by infusion of a donor stem cell graft on day 0. Postgrafting immunosuppression consisted of cyclosporin A and mycophenolate mofetil. At a median follow-up of 443 days, the overall survival was 53%, relapse incidence was 27%, and nonrelapse mortality was 27%. The incidence of severe acute (grade III/IV) graft-versus-host disease (GVHD) was 27%, and that of (predominantly mild) chronic GVHD was 60%. Immunomonitoring studies revealed that specific CD8(+) T cell responses against epigenetically silenced tumor-associated antigens (TAAs), including cancer-testis antigens (MAGE-A1/A2/A3 and PRAME) and RHAMM, occurred more frequently in patients who had received Dec/Flu/TBI conditioning (8 of 11 patients) compared with a control group of patients who had received only Flu/TBI conditioning (2 of 9 patients). In summary, Dec/Flu/TBI conditioning proved feasible and effective and enhanced the induction of TAA-reactive CD8(+) T cell responses in vivo, which may contribute to disease control post-transplantation.