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The erythropoietin (Epo)-erythroferrone (ERFE)-hepcidin axis coordinates erythropoiesis and iron homeostasis. While mouse studies have established that Epo-induced ERFE production represses hepcidin synthesis by inhibiting hepatic BMP/SMAD signaling, evidence for the role of ERFE in humans is limited. To investigate the role of ERFE as a physiological erythroid regulator in humans, we conducted two studies. First, 24 males were given six injections of saline (placebo), recombinant Epo (rhEpo) at a dose of 20 IU/kg (micro-dose) or rhEpo at 50 IU/kg (low dose). Second, we quantified ERFE in 22 subjects exposed to high altitude (3800 m) for 15 h. In the first study, total hemoglobin mass (Hbmass) increased after low- but not after micro-dose injections, when compared to the mass after placebo injections. Serum ERFE levels were enhanced by rhEpo, remaining higher than after placebo for 48 h (micro-dose) or 72 h (low-dose) after injections. Conversely, hepcidin levels decreased when Epo and ERFE rose, before any changes in serum iron parameters occurred. In the second study, serum Epo and ERFE increased at high altitude. The present results demonstrate that in healthy humans ERFE responds to slightly increased Epo levels not associated with Hbmass expansion and downregulates hepcidin in an apparently iron-independent way. Notably, ERFE flags micro-dose Epo, thus holding promise as a novel biomarker of doping.

Background: Genomic complexity can predict the clinical course of patients affected by chronic lymphocytic leukemia (CLL) with a normal FISH. However, large studies are still lacking. Here, we analyzed a large series of CLL patients and also carried out the so far largest comparison of FISH versus single-nucleotide polymorphism (SNP) array in this disease. Patients and methods: SNP-array data were derived from a previously reported dataset. Results: Seventy-seven of 329 CLL patients (23%) presented with a normal FISH. At least one large (>5 Mb) genomic aberration was detected by SNP array in 17 of 77 patients (22%); this finding significantly affected TTT. There was no correlation with the presence of TP53 mutations. In multivariate analysis, including age, Binet stage, IGHV genes mutational status and large genomic lesion, the latter three factors emerged as independent prognosticators. The concordance between FISH and SNP array varied between 84 and 97%, depending on the specific genomic locus investigated. Conclusions: SNP array detected additional large genomic aberrations not covered by the standard FISH panel predicting the outcome of CLL patients.

Abstract 3906 The clinical course of CLL patients ranges from an indolent and chronic disease to a rapidly progressing leukemia or lymphoma necessitating aggressive treatment. Very recent data have shown that genomic complexity evaluated by conventional karyotyping with DSP30/IL2 stimulation (Rigolin et al, Blood 2012) can be helpful in the prediction of the clinical course of patients with a normal fluorescence in situ hybridization (FISH) panel according to Dšhner et al (NEJM 2000). However, large studies investigating the impact of genomic complexity on the clinical course and possible correlations with other clinical parameters at time of diagnosis are still lacking. Therefore, we analyzed the role of genomic complexity in a large series of 329 CLL patients with available clinical data. Also, since SNP-array might soon represent an alternative to standard FISH in the clinical routine, we performed the so far largest comparison of FISH versus SNP-array in CLL. Methods. Copy-number data, obtained using the Affymetrix Human Mapping GeneChip 6.0 arrays (SNP6), were derived from our previously reported CLL dataset (Rinaldi, Mian, Kwee et al, BJH 2011). The FISH panel interrogated deletions at 13q14.3, 11q22, 17p13 and trisomy 12. CLL diagnosis and management were based on the NCI Working group criteria (Hallek et al., Blood 2008). Real-time PCR on genomic DNA was performed to validate discordant FISH/SNP6 results. Results. Seventy-seven of the 329 CLL patients (23%) presented a normal FISH. Among those, 17 patients (22%) had at least one large (>5 Mb) genomic aberration, different from those described by Dšhner et al (NEJM 2000). There was no correlation with the presence of TP53 mutations, since 13/13 were wtTP53. The DNA gains or losses did not occur at specific genomic loci, and their presence significantly affected the TTT (P= 0.0010; R=2.8; 95% CI, 1.5–5.5) (Figure 1), but not overall survival (OS) (p= 0.098; HR 2.3; 95% CI, 0.83–6.6). In a multivariate analysis including age, Binet stage, IGHV genes mutational status and the large genomic lesions, the latter three factors emerged as independent prognosticators for TTT with a significance of P The concordance between FISH and SNP-array results was 93% for all analyzed genomic regions: 97% for trisomy 12, 96% for del 11q, 95% for del 17p and 84% for del 13q. False positive FISH results were observed for del 13q, while among the 18 cases with 17p loss by FISH half of the 10 cases with less than 40% of nuclei carrying the lesion were classified as normal by SNP6. We applied the FISH-based prognostic model developed by Dšhner et al (NEJM 2000) to our cohort classifying the 329 patients using results obtained by FISH or by SNP6: the Kaplan-Meier curves were comparable between FISH and SNP-array, both for OS as for TTT, and the log-rank test was highly significant for both approaches. Conclusions. Patients with a normal FISH but with large genomic lesions detected by SNP-array have a worse TTT. As a whole, SNP-array has a high sensitivity and specificity and is able to identify the most important known prognostic genomic aberrations of CLL. A validation in prospective trials is needed. Disclosures: No relevant conflicts of interest to declare.

The goal of this prospective randomized single-center study was the comparison of safety and efficacy of high-dose oral/intravenous fluconazole (400 mg daily) (group A) with oral nystatin plus miconazole inhalations (group B) in the prevention of fungal infections on a hemato-oncological isolation Ward. Of 157 patients admitted to the isolation ward during the study period only 90 (57%) were eligible for randomization; 22 (14%) had a fungal infection at admission. Of the 90 randomized patients, 89 were evaluable, 43 in group A and 46 in group B. The age, sex, diagnosis, planned therapy and risk factors for fungal infections at admission as well as the duration of neutropenia were in the same proportions in both groups. Oral thrush and mucocutaneous candidiasis were prevented in all patients of both groups, and 29 patients (32%: 17 in group A, 12 in group B) were discharged after successful prophylaxis (NS). Empiric amphotericin B was given according to predetermined criteria to 45 patients (51%: 23 group A, 22 group B; NS). Fluconazole significantly delayed the time before the start of intravenous amphotericin B. It was begun after a median of 10 days (0–45 days, range) of neutropenia below 0.5x109 granulocytes/l in group A and 7.5 days (0–26, range) in group B (P