ALBERT

Description: To improve the results of allogeneic SCT for high-risk AML and MDS, the FLAMSA-RIC conditioning regimen for allogeneic SCT combines cytoreductive chemotherapy (fludarabine, HD AraC, amsacrine), followed three days later by reduced intensity conditioning (4Gy TBI/EDX). Since in particular patients with an unfavorable karyotype seemed to benefit from this approach (Schmid et al., JCO, 2005), we analysed the outcome of 172 patients with poor risk cytogenetics according to NCCN criteria, who had been allografted following FLAMSA-RIC conditioning in 11 European centres between 1999 and 2008. Median time from diagnosis to transplantation was 5 months. Donors were matched siblings, matched unrelated, or mismatched unrelated donors in 34%, 47%, and 19%. Patients suffered from progressive MDS (10%), de novo AML (47.5%), or secondary AML (43.5%). SCT was performed upfront, after primary induction failure, in CR1 and in relapsed disease in 17%, 33%, 22% and 28% of patients, respectively. Median patient age was 53 (18–71) years. 95 patients (56%) had a complex aberrant karyotype, 55 and 65 had abnormalities of chromosome 5 (−5/5q-) and 7 (−7/7q-), respectively. After a median follow up of 20 months, overall survival (OS) at 2 and 4 years was 46.4% and 40.5%, the respective leukemia-free survival was 37.7% and 32.0%. Causes of death were leukemia in 30%, and non-relapse mortality in 21%. Encouraging results were observed in patients with chromosome 7 aberrations or with a complex karyotype leukemia (4y OS=49.3% and 40.3%). In contrast, results were inferior in patients with chromosome 5 aberrations (4y OS=30%), mainly due to an increased rate of leukemia-associated death (p=.008). Patiens with MDS, who received allogeneic SCT as first line treatment, achieved a 4y OS of 80% despite unfavorable cytogenetics. Unlike, patients with secondary AML after MDS had an inferior outcome (4y OS=28%, p=.018). In a Cox regression model, a stage of remission at transplantation, a 8/8 or 10/10 matched family or unrelated donor, and lack of monosomy 5 or deletion 5q were associated with superior OS (p=.025, .05, and .05). In conclusion, allogeneic SCT following the FLAMSA-RIC regimen is a highly effective treatment for MDS and AML with unfavorable karyotype, comparing favourably with published data. In MDS, SCT should be performed before transformation into sAML. Long term remission is achieved in a substantial percentage of patients with complex karyotype disease and aberrations of chromosome 7. Aberrations of chromosome 5 may require alternative or additive strategies.

Description: Introduction: Keratinocyte Growth factor (KGF) prophylaxis reduces the extent and duration of mucosal barrier injury following intensive chemotherapy. Following this prophylaxis a marked reduction of infections and consecutively the need for antibiotic treatment can be observed. The extent of oral mucositis (OM) is easely to access. The extent of instestinal musocitis (IM) is more difficult to determine: The serum level of Citrulline, an intermediate product of the uric acid cycle mainly synthesized in the small intestine, serves as a marker of small intestine injury. Aim of the present study was to determine the extent of OM and IM before and after the introduction of KGF-prophylaxis in their treatment. METHODS: In 09/2006 KGF (60μg/kg body weight per day, for 3 days before conditioning therapy respectively after HSCT) was introduced at our institution on a compassionate use basis. Five months before the introduction and thereafter the extent of OM and IM in autologous and allogeneic HSCT was evaluated prospectively. Beside routine clinical and laboratory values including the daily oral mucositis score (DMS) and daily gut score (DGS) the plasma citrulline level was determined in week 1 (W1), week 2 (W2) and week 3 (W3) following HSCT. Moreover the dosage of therapeutic intravenous (i.v.) antibiotic treatment with meropeneme, piperacilline/combactam and teicoplanin in addition to antibiotic prophylaxis was noted. Pt with oropharyngeal radiotherapy were excluded from analysis. RESULTS: Until 04/2007 36 pt were evaluated. 27 pt underwent autologous and 9 allogeneic HSCT. 13 of the autologous and 6 of the allogeneic transplanted pt received KGF. In pt with KGF clinically significant OM and moderate to severe IM were seen less often (W1: 1/19 pt vs. 3/17 pt and W2: 1/19 pt vs. 2/17 pt without KGF). These differences were statistically non significant. Citrulline serum levels (in μmol/l) were significantly higher in pt receiving KGF (W2: average 16.8 vs. 15.9 in pt without KGF (p = 0.02)). The therapeutic use of i.v. antibiotics was lower for pt receiving KGF (average of 10.5 days vs. 26.8 days for pt without KGF (p = 0.0001)). Subgroup analysis confirmed the described tendencies in autologous HSCT. SUMMARY: Even in this small number of pt a positive effect of KGF on oral and intestinal mucositis was detectable. The reduced need for therapeutic i.v. antibiotics seen as a tendency in this study should be re-evaluated in a prospective pharmacoeconomic study to prove cost effectiveness of KGF treatment.