Low relapse risk in poor risk AML after conditioning with 10-day decitabine, fludarabine and 2 Gray TBI prior to allogeneic hematopoietic cell transplantation.

Patients with poor risk acute myeloid leukemia (AML) have a dismal outcome. We hypothesized that combining decitabine with a standard non-myeloablative (NMA) conditioning regimen prior to allogeneic hematopoietic cell transplantation (allo HCT), might decrease the relapse incidence. We conducted a multicenter prospective phase II study (NCT02252107) with 10-day decitabine (20 mg/m(2)/day) integrated in a standard non-myeloablative conditioning regimen (3 days fludarabine 30 mg/m(2) with 2 Gray total body irradiation (TBI)). Patients with AML ≥ 18 years in 1st (in)complete remission (CR/CRi) with a poor or very poor risk profile, as defined by the HOVON-132 protocol, were eligible. Results: Forty-six patients (median age 60; range 23-74) were included. Median follow up time was 44 months (range 31-65 months). The cumulative 1-year incidence of relapse and NRM were respectively 23% and 11%. Incidence of grade III-IV acute graft-vs-host-disease (GVHD) and severe chronic GVHD were 13% and 20%, respectively. One-year OS was 70%. Application of ELN 2017 risk classification to the study cohort revealed a cumulative one-year relapse rate of respectively 31% and 13% for the adverse and intermediate risk patients. To conclude, the 10-day DEC/FLU/TBI conditioning regimen prior to allo HCT in poor risk AML patients is effective and feasible

Intestinal Damage Determines the Inflammatory Response and Early Complications in Patients Receiving Conditioning for a Stem Cell Transplantation

Contains fulltext : 87954.pdf (publisher's version ) (Open Access)BACKGROUND: Stem cell transplantation (SCT) is still complicated by the occurrence of fever and inflammatory complications attributed to neutropenia and subsequent infectious complications. The role of mucosal barrier injury (MBI) of the intestinal tract therein has received little attention. METHODS: We performed a retrospective analysis in 163 SCT recipients of which data had been collected prospectively on intestinal damage (citrulline), inflammation (C-reactive protein), and neutrophil count. Six different conditioning regimens were studied; 5 myeloablative (MA) and 1 non-myeloablative (NMA). Linear mixed model multivariate and AUC analyses were used to define the role of intestinal damage in post-SCT inflammation. We also studied the relationship between the degree of intestinal damage and the occurrence of early post-SCT complications. RESULTS: In the 5 MA regimen there was a striking pattern of inflammatory response that coincided with the occurrence of severe intestinal damage. This contrasted with a modest inflammatory response seen in the NMA regimen in which intestinal damage was limited. With linear mixed model analysis the degree of intestinal damage was shown the most important determinant of the inflammatory response, and both neutropenia and bacteremia had only a minor impact. AUC analysis revealed a strong correlation between citrulline and CRP (Pearson correlation r = 0.96). Intestinal damage was associated with the occurrence of bacteremia and acute lung injury, and influenced the kinetics of acute graft-versus-host disease. CONCLUSION: The degree of intestinal damage after myeloablative conditioning appeared to be the most important determined the inflammatory response following SCT, and was associated with inflammatory complications. Studies should explore ways to ameliorate cytotoxic therapy-induced intestinal damage in order to reduce complications associated with myeloablative conditioning therapy

Features, Causes and Consequences of Splanchnic Sequestration of Amino Acid in Old Rats

RATIONALE: In elderly subjects, splanchnic extraction of amino acids (AA) increases during meals in a process known as splanchnic sequestration of amino acids (SSAA). This process potentially contributes to the age-related progressive decline in muscle mass via reduced peripheral availability of dietary AA. SSAA mechanisms are unknown but may involve an increased net utilization of ingested AA in the splanchnic area. OBJECTIVES: Using stable isotope methodology in fed adult and old rats to provide insight into age-related SSAA using three hypotheses: 1) an increase in protein synthesis in the gut and/or the liver, 2) an increase in AA oxidation related to an increased ureagenesis, and 3) Kupffer cell (KC) activation consequently to age-related low-grade inflammation. FINDINGS: Splanchnic extraction of Leu (SPELeu) was doubled in old rats compared to adult rats and was not changed after KC inactivation. No age-related effects on gut and liver protein synthesis were observed, but urea synthesis was lower in old rats and negatively correlated to liver Arg utilization. Net whole-body protein synthesis and arterial AA levels were lower in old rats and correlated negatively with SPELeu. CONCLUSION: SSAA is not the consequence of age-related alterations in ureagenesis, gut or liver protein synthesis or of KC activity. However, SSAA may be related to reduced net whole-body protein synthesis and consequently to the reduced lean body mass that occurs during aging

Stem cell transplantation complications.

<p>OVS = oral viridians streptococci, CoNS = coagulase-negative staphylococci, IA = invasive <i>Aspergillosis</i>, ALI = acute lung injury, acute GvHD = acute graft-versus-host disease. Grading of acute GvHD was done according to the criteria of <i>Przepiorka et al.</i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015156#pone.0015156-Przepiorka1" target="_blank">[27]</a> and probable/proven IA was defined according to EORTC/MSG consensus definitions <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015156#pone.0015156-dePauw2" target="_blank">[25]</a>.</p

Summary of the time course of citrulline (A) and CRP (B) for all 6 regimens.

<p>Day 1 is the day of start of conditioning. To correct for unobserved citrulline and CRP values we modeled the course of citrulline and CRP as described in methods. 1 = HDM, 2 = BEAM, 3 = Ida-Cyclo-TBI, 4 = Cyclo-ATG-TBI, 5 = Cyclo-TBI, 6 = Cyclo-Flu. Mean CRP in mg/L, mean citrullline in µmol/L.</p

Pearson correlation between the mean degrees of neutropenia (NP in days) and inflammation (CRP_AUC) versus intestinal damage (Citrulline_AUC) and inflammation (CRP_AUC) over the different regimens.

<p>1 = HDM, 2 = BEAM, 3 = Ida-Cyclo-TBI, 4 = Cyclo-ATG-TBI, 5 = Cyclo-TBI, 6 = Cyclo-Flu.</p

Conditioning regimens.

<p>Abbreviations: od; once daily, bd; two times daily, TBI = total body irradiotion, MA = myeloablative, NMA = non-myeloablative.</p

General characteristics.

<p>Characteristics of patients, stem cell transplantation and general outcome measures of intestinal damage (citrulline), inflammation (CRP and fever), and neutropenia (neutrophil count ≤0.5×10⁹/L) for each conditioning regimen.</p><p>*Citrulline was measured 3 times weekly.</p>#<p>Only those patients included with citrulline levels below 10 µmol/L.</p>&<p>Based on estimated values. MA = myeloablative, NMA = non-myeloablative, CRP = C-reactive protein, MM = multiple myeloma, NHL = non-Hodgkin lymphoma, CLL = chronic lymphatic leukemia, AML/ALL = acute myeloid and lymphatic leukemia, MDS = myelodysplastic syndrome, CML/MPD = chronic myeloid leukemia/myeloproliferative disease.</p