ALBERT

Description: The presence of residual leukemic cells was studied using metaphase-fluorescence in situ hybridization (FISH) in 22 patients with acute myeloid leukemia treated with chemotherapy only or chemotherapy followed by allogeneic bone marrow transplantation. The patients were followed up during their complete remission (CR) for 4 to 108 months (median, 21 months). A total of 88 BM samples was studied. In most of the samples more than 1,000 metaphase cells were analyzed. Residual leukemic cells were detected in 9 of 22 patients (41%). All patients who had an increasing and/or persisting level of abnormal cells in two or more subsequent samples or whose initial samples contained more than 1% of abnormal cells relapsed with one exception, in whom the later subsequent samples showed disappearance of abnormal cells. The time span before the first positive sample seems to be insignificant with regard to the outcome of relapse. Absence or single occurrence of abnormal cells followed by their disappearance was in agreement with CR in all the cases (16 patients). Our results indicate that metaphase-FISH is a reliable tool in the quantitation of residual leukemic cells and provides valuable prognostic information for patients with AML.

Description: Non-HLA polymorphisms (NHP) influence risk of GVHD and outcome of allogeneic hematopoietic stem cell transplants (HSCT) however their influence on GvHD vs GvL remains to be defined. A cohort of 291 CML HLA matched sibling transplants with known clinical risk factors; eg stage of disease, gender mismatch (female donor/male recipient), patient age and time from diagnosis to transplant as defined by the EBMT risk score, were typed via SNPs or microsatellites for cytokines (IL-1Ra, IL-4, IL-6, IL-10, IFNγ, TNFα, TNFR 11), steroid hormone receptors (VDR and ERα) and NOD2/CARD15 mutations. TNFRII-196 allele R; IL-10 ATC/ACC; IL-1 Ra (allele 2) and IL-4T were significantly associated with survival using univariate analysis. Two clinical Cox proportional hazards models were generated for the statistical analysis and used as a basis for further development: (i) using the EBMT risk score as a single variable on an ordinal scale or (ii) using the individual clinical factors of the EBMT risk score as categorical variables. After step-wise variable selection using the significant genetic factors as candidates, the resulting multivariate models indicated that absence of TNFRII-196 R, i.e. down regulation of TNF in the recipient, absence of IL-10 ATC/ACC, i.e. intermediate IL-10 production in the donor and presence of IL-1Ra (allele 2) i.e. down regulation of IL-1 in the donor were associated with poor outcome. The addition of the genetic variables significantly improved the preferred model containing the EBMT risk score as a single variable. The Goodness of Fit of the models was assessed by Kaplan-Meier curves showing clinically relevant differences between good, intermediate and poor prognostic groups. The worst prognostic scores included the absence of ATA/ACC in the donor, evidenced by a steep change in survival probability. Relapse was associated with clinical factors; absence of female to male transplants; absence of bone marrow transplants and presence of T cell depletion but no significant association was found with genetic factors. This study suggests that distinct high risk patterns of NHP of patients and donors can be defined, which influences survival due to factors associated with an increased risk of GvHD without the potential benefit of increased GvL response. Data add to the clinical factors (eg age, sex, multiparity of the donor) where an unrelated donor might be the preferred choice compared to a high risk sibling donor.

Description: Introduction: Hepatic veno-occlusive disease (VOD) is one of the most significant regimen-related toxicities of stem cell transplantation (SCT), which when complicated by multi-organ failure (MOF) has a case fatality rate 〉90%. Defibrotide (DF) is a polydisperse oligonucleotide, with anti-thrombotic, anti-ischemic and thrombolytic properties, especially on microvasculature. Results in earlier studies of DF therapy for VOD/MOF have consistently shown manageable toxicity with promising complete response (CR) rates and D+100 survival post SCT. We report the results of the largest compassionate use program (CUP) performed to date. Methods: Physicians in Europe requesting DF for the treatment of pts with VOD obtained the drug on a named patient basis and were requested to collect data by a standardized CRF. Patients (pts) were reviewed to identify the nature and frequency of Suspected Adverse Drug Reactions (SADR). CR and D+100 survival post-SCT were assessed with CR defined as bilirubin

Description: Relapsed AML after allogeneic SCT has a poor prognosis. So far, no standard therapy could be defined. Donor lymphocyte transfusion (DLT) has been effective in a minority, however, no data is available to identify patients who will benefit from the procedure. Neither, the outcome of patients treated with or without DLT have been compared. We retrospectively evaluated overall survival (OS) of 489 adults with de novo AML in hematological relapse after SCT, receiving DLT (n=190) or not (n=299). DLT and noDLTgroups were well balanced in terms of patient age (median:37y in both groups), donor age, cytogenetics (good:5vs7%, intermediate:83vs79%, poor:12%vs14%), WBC at diagnosis, donor type (geno-id:71vs72%, MUD:18% both, mismatched:11vs10%), status at transplantation (CR1:38vs41%, CR2:13vs15%, advanced:49vs44%), conditioning, source of stem cells, and time from transplant to relapse (5vs4.5 months). However, DLT patients had a median of 39% BM blasts, as compared to 54% for the noDLT group (p=0.03). Follow-up was 32 and 30 months. Within the DLT group, chemotherapy was additionally given in 130 cases. Nevertheless, only 33% of patients received DLT in CR or aplasia, 67% had measurable disease. AGvHD developed in 41% of patients following DLT. CR and PR were achieved in 31.1% and 4.8% of DLT patients. In a multivariate analysis, younger patient age ( 5 months) from transplant to relapse (HR=7.74,p=0.002) were associated with better OS after DLT. When comparing the outcome of patients receiving or not DLT, OS at 2 years was 10±1% for the entire cohort, 18±3% for DLT and 6±1% for noDLT (p

Description: Abstract 488FN2 The role of ursodeoxycholic acid (UDCA) in the prevention of hepatic complications after allogeneic stem cell transplantation was studied in a prospective randomized open-label multicenter trial. A total of 242 patients were allocated to receive (n=123) or not to receive (n=119) UDCA at the dose of 12 mg/kg/day from the day preceding the conditioning until day 90 post-transplantation. The median age was 39, range 1–59 years. 231 patients had a malignant hematological disease. 140 patients had a low-risk disease (acute leukemia in CR1, CML in CP1, or non-malignant disorder), 102 high-risk disease (all other). Of the donors 132 were siblings, 2 other related and 108 unrelated. TBI-containing conditioning was given to 219 patients. 190 patients received a bone marrow graft and 52 a blood stem cell graft. As GvHD prophylaxis 235 patients were given cyclosporine and methotrexate with (n=112) or without (n=123) corticosteroid. There were no significant differences in patient characteristics between the study groups. The results were reported after 1-year follow-up (Blood 100: 1977–1983, 2002). In the group given UDCA prophylaxis the survival was significantly better, the incidence of acute GvHD was lower, there were fewer patients with high bilirubin and ALAT levels, the non-relapse mortality was lower, and there were fewer deaths in GvHD. We report here the long-term outcome. The median follow-up of living patients was 155 (range 37–184) months. Two patients were lost early (12–15 months) for follow-up. The survival difference seen at one year remained similar in the long-term follow-up. At 10 years, 48 % of the patients given UDCA and 38 % of the control patients survived (p=0.037). The survival difference was highly significant among the low-risk patients (63 % vs. 46 %, p=0.019) but there was no difference among the high risk patients (25 % vs. 29 %). In the total patient material, the cumulative incidence of non-relapse mortality was significantly lower among the patients given UDCA (28 % vs. 41 %, p=0.031). There was no significant difference in the cumulative incidence (58 % in the UDCA group vs. 68 % in the control group among patients at risk, p=0.47) or severity of chronic GvHD. In the long-term follow-up there were no significant differences in liver problems between the study groups. The cumulative incidence of relapse did not differ significantly between the arms. In the UDCA group 23 % and in the control group 20 % of the patients had a relapse; among low risk patients 14 % vs. 12 %, respectively. There were seven secondary cancers in both study arms. These long-term results continue to support the useful role of UDCA in the prevention of transplant-related complications in allogeneic stem cell transplantation. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: The reported incidences of sinusoidal obstruction syndrome/veno-occlusive disease of the liver (VOD) have varied widely. In recent reviews the present incidence has been stated to be up to 10-15 %. The differences in the incidences may be due to different patient materials and transplantation methods or differences in the application and interpretation of diagnostic criteria. Modified Seattle criteria (McDonald et al 1993) or Baltimore criteria (Jones et al 1986) are used to establish the diagnosis. The diagnosis is based on a combination of clinical criteria. However, the diagnosis of VOD should only be made if there are no other conditions that could explain the clinical findings. More than one condition causing liver problems may be present at the same time, leaving space for subjective interpretation that could essentially affect the incidence of this disorder. Along with the improving opportunities for prophylaxis and treatment of VOD, it is important to have a correctpicture of its incidence. We evaluated the differential diagnostic component of VOD diagnosis in our single-center material. Patients: The hospital notes of 300 consecutive adult patients treated with allogeneic stem cell transplantation between March 2011 and February 2015 at the Helsinki University Hospital were retrospectively reviewed. All but one had a malignant hematological disease. The most common diagnoses were AML 106, ALL 48, MM 46, NHL 34, and MDS 24. The total of 135 patients (45%) received conventional myeloabative conditioning, CyTBI (n=79) or BuCy (n=56), 151 were given treosulfan in myeloablative (n=77) or reduced (n=74) dose with fludarabine, 5 received BuFlu and 9 other regimen. Of the donors 75 % were unrelated, and 77 % of the grafts were from peripheral blood. All patients received ursodeoxycholic acid (UDCA) prophylaxis. GvHD prophylaxis consisted of CsA and a short course of MTX. ATG was given in transplantations from unrelated donor. Methods: We identified all patients who had a total serum bilirubin concentration exceeding 34 µmol/l during the first three weeks after the transplantation. Among them we evaluated whether they had a weight increase of more than 2 % or 5 % compared to the admission weight. We also registered the clinical notes of liver enlargement, upper right abdomen pain and ascites as well as ultrasound examinations. Results: Of the 300 patients, 54 had a serum bilirubin concentration exceeding 34 µmol/l within three weeks post-transplantation. The peak bilirubin concentration was 35-193 (median 47) µmol/l. Of these patients, 43 showed a weight gain exceeding 2 % and 29 patients exceeding 5 % of the admission weight. Thus, forty-three patients fulfilled the minimum modified Seattle criteria with the 2 % weight gain criterion and 29 with the 5 % criterion (modification, Corbacioglu et al 2012). Two patients had enlarged liver and right upper quadrant pain. No case of abnormal venous blood flow was seen. According to institutional policy, preemptive treatment with defibrotide according to bilirubin levels was started in 10 patients but in most cases discontinued within a few days based on the clinical course. Twenty-eight (65 %) of the 43 patients fulfilling the minimal VOD criteria had other clinical conditions that were regarded by the treating team as a plausible cause for the findings: infection 22, non-conditioning drug effect 4, cholecystitis or cholestasis 2, engraftment syndrome 2, GvHD 1, and hemolysis 1. In the remaining 15 patients there was no obvious alternative cause. Thirteen of these cases were mild, showing no hepatomegaly, and they had not been labelled as VOD. Conclusion: According to the modified Seattle criteria, 15 patients (2% weight criterion) or 10 patients (5 % weight criterion), without an alternative cause to the clinical findings, had VOD. Two patients fulfilled the Baltimore criteria, but as one of them had a simultaneous septic infection, the diagnosis of VOD could not be confirmed. Therefore, depending on the criteria used and the differential diagnostic interpretations, the incidence of VOD in this material was between 5 % and 0.3 %. All cases were mild. UDCA prophylaxis and preemptive defibrotide treatment probably affected the incidence. Differences in differential diagnostic interpretations may contribute significantly to the variable incidences of VOD reported. Disclosures No relevant conflicts of interest to declare.