Conflict of interest:The authors declare no relevant conflict of interest in relation to the work described.AML with biallelic mutations in the CCAAT/enhancer-binding-protein-alpha gene (CEBPA bi ) 1 has now been included in the 2016 revision of the World Health Organization (WHO) 2 classification of myeloid neoplasms as a definite entity due to its association with distinct 3 biological and clinical features as well as its prognostic significance. 1 Mutations in CEBPA 4 (CEBPA mut ) predominantly occur in acute myeloid leukemia (AML) with normal cytogenetics 5 (CN; ~15%), and approximately 60% of the mutated cases carry biallelic mutations. Several 6 studies concordantly showed that in particular patients with CEBPA bi have a favorable 7 outcome compared to monoallelic mutated or wildtype CEBPA (CEBPA wt ) patients. 2,3 8Recently, mutations in the transcription factor GATA2 were identified as genetic lesions 9 potentially cooperating with CEBPA bi with a co-incidence of 18-41%. 4,5 Both, CEBPA and 10 GATA2 are involved in the control of proliferation and differentiation of myeloid progenitors, 11 and germline mutations in both genes have been found predisposing affected individuals for 12 the development of AML. 3,6 GATA2 knockout mice suffer from severe anemia and die around 13 3 day ten of embryonic development. 7 Data from functional studies showed that there is an 14 important interplay between the two genes, e.g. through direct protein-protein-interaction. 8 In 15addition, the C/EBPα dependent activation of target genes is enhanced through 16 coexpression of GATA2 wt . Finally, preliminary data suggest that GATA2 mut allow further 17 refinement of CEBPA mut AML patients with regard to their clinical outcome. 5 18In our study we evaluated the frequency and the clinical impact of GATA2 mut within a large 19 cohort of CEBPA mut AML patients. In total 202 AML patients (age 18 to 78 years) with 20 CEBPA single (CEBPA sm , n=89) or CEBPA bi (n=113) mutations were analyzed for the 21 presence of concurrent GATA2 mut . All patients were enrolled in one of 6 AMLSG treatment 22 trials applying intensive therapy [AMLHD93 n=15; 9 AMLHD98A (NCT00146120) n=53; 23 AMLHD98B n=13; 10 AMLSG 07-04 (NCT00151242) n=74; AMLSG 06-04 (NCT00151255) 24 n=25 and AMLSG 12-09 (NCT01180322) n=22]. The clinical studies were approved by the 25 local ethics review committees and all patients gave informed consent for treatment, 26 molecular analysis and cryopreservation of leukemia samples according to the Declaration of 27Helsinki. In the AMLHD 98B-and AMLSG 06-04 trials patients over the age of 60 were 28 enrolled. The AMLSG 12-09 trial had no upper age limit. In the remaining trials patients 18 to 29 60 years of age were eligible. GATA2 mut screening was performed using a DNA-based PCR-30 assay covering exons 2 to 6 followed by Sanger sequencing. 4 31Among the 202 CEBPA mut AML patients, we identified 42 GATA2 mut in 40 of the 202 patients 32 (20%). Within the subgroup of CEBPA bi mutated patients 38 GATA2 mut were identified in 36 33 o...

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Biochemical modulation of 5-fluorouracil (5-FU) by folinic acid (FA) increases the response rate in patients with metastatic colorectal cancer compared to 5-FU alone. Phase II trials also demonstrated increased efficacy when interferon was added to 5-FU. In two consecutive trials, 76 patients were treated on days 1-5 with FA 200 mg/m² plus interferon 5 × 10⁶ U/m² and 5-FU 350 mg/m² as intravenous bolus injection (n = 33, regimen A) or 5-FU 500 mg/m² as 2-hour infusion (n = 43, regimen B), repeated every 3 weeks with individual 5-FU dose escalation in steps of 50 (regimen A) or 100 mg/m² (regimen B). In regimen A 5-FU dose reduction to 300 mg/m² due to toxicity was necessary in 49% of the patients; in regimen B a 5-FU dose of 600 mg/m² or above was tolerated by 70% of the patients. Dose-limiting toxicity was severe mucositis and/or diarrhea. Objective responses were observed in 5 of 33 patients (15%) in regimen A (3-28%, 95% confidence interval) and 7 of 41 patients (17%) in regimen B (5-29%, 95% confidence interval). Median time to progression was 4.7 and 4.8 months, and median survival 9.9 and 11.4 months for regimens A and B, respectively. Prolonged 5-FU administration over 2 h allows the administration of a higher 5-FU dose compared to bolus injection with no apparent improvement in antineoplastic efficacy. The addition of interferon to the combination of 5-FU plus FA in this dose and schedule does not seem to improve the response rate but appears to increase treatment toxicity.

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