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Purpose: Hydroxyurea (HY) is a reference treatment of advanced myeloproliferative neoplasms. We conducted a randomized phase III trial comparing decitabine (DAC) and HY in advanced myeloproliferative chronic myelomonocytic leukemias (CMML)., Patients and Methods: Newly diagnosed myeloproliferative CMML patients with advanced disease were randomly assigned 1:1 to intravenous DAC (20 mg/m 2 /d days 1-5) or HY (1-4 g/d) in 28-day cycles. The primary end point was event-free survival (EFS), events being death and acute myelomonocytic leukemia (AML) transformation or progression., Results: One-hundred seventy patients received DAC (n = 84) or HY (n = 86). Median age was 72 and 74 years, and median WBC count 32.5 × 10 9 /L and 31.2 × 10 9 /L in the DAC and HY arms, respectively. Thirty-three percent of DAC and 31% of HY patients had CMML-2. Patients received a median of five DAC and six HY cycles. With a median follow-up of 17.5 months, median EFS was 12.1 months in the DAC arm and 10.3 months in the HY arm (hazard ratio [HR], 0.83; 95% CI, 0.59 to 1.16; P = .27). There was no significant interaction between treatment effect and blast or platelet count, anemia, CMML Prognostic Scoring System, Groupe Francophone des Myelodysplasies, or CMML Prognostic Scoring System-mol risk. Fifty-three (63%) DAC patients achieved a response compared with 30 (35%) HY patients ( P = .0004). Median duration of response was similar in both arms (DAC, 16.3 months; HY, 17.4 months; P = .90). Median overall survival was 18.4 months in the DAC arm and 21.9 months in the HY arm ( P = .67). Compared with HY, DAC significantly reduced the risk of CMML progression or transformation to acute myelomonocytic leukemia (cause-specific HR, 0.62; 95% CI, 0.41 to 0.94; P = .005) at the expense of death without progression or transformation (cause-specific HR, 1.55; 95% CI, 0.82 to 2.9; P = .04)., Conclusion: Compared with HY, frontline treatment with DAC did not improve EFS in patients with advanced myeloproliferative CMML (ClinicalTrials.gov identifier: NCT02214407)., Competing Interests: Raphael ItzyksonHonoraria: AbbVie, Astellas Pharma, Celgene/Bristol Myers Squibb, Novartis, ServierConsulting or Advisory Role: Amgen, Celgene/Bristol Myers Squibb, Daiichi Sankyo Europe GmbH, Novartis, ServierResearch Funding: Janssen (Inst), Novartis (Inst) Valeria SantiniHonoraria: Celgene/Bristol Myers Squibb, NovartisConsulting or Advisory Role: Celgene/Bristol Myers Squibb, Novartis, Menarini, Takeda, Gilead Sciences, AbbVie, Syros Pharmaceuticals, ServierResearch Funding: Celgene (Inst)Travel, Accommodations, Expenses: Janssen-Cilag, Celgene Sylvain ThepotHonoraria: Astellas Pharma, Novartis, AbbVie, BMSiTravel, Accommodations, Expenses: Amgen, AbbVie Lionel AdesHonoraria: Celgene, AbbVie, Jazz Pharmaceuticals, BerGenBio, Silence Therapeutics, NovartisResearch Funding: Celgene (Inst) Aristoteles GiagounidisStock and Other Ownership Interests: Novartis, RocheHonoraria: Amgen, Novartis, Bristol Myers Squibb/CelgeneConsulting or Advisory Role: Bristol Myers Squibb/Celgene Michael LübbertConsulting or Advisory Role: Syros Pharmaceuticals, AbbVieResearch Funding: Johnson & Johnson (Inst) Ulrich GermingHonoraria: Celgene, Novartis, Jazz PharmaceuticalsConsulting or Advisory Role: CelgeneResearch Funding: Celgene (Inst), Novartis (Inst) Anna Maria PelizzariTravel, Accommodations, Expenses: Janssen-Ortho Sophie ParkHonoraria: Novartis/Ipsen, Bristol Myers Squibb/CelgeneConsulting or Advisory Role: Novartis, Pfizer, Bristol Myers Squibb/CelgeneResearch Funding: Pfizer, TakedaTravel, Accommodations, Expenses: Pfizer, Novartis Nadja JaekelHonoraria: Novartis Georgia MetzgerothHonoraria: Roche Pharma AG, Novartis, GlaxoSmithKlineConsulting or Advisory Role: GlaxoSmithKline Francesco OnidaTravel, Accommodations, Expenses: Takeda, Kyowa Kirin International, Medac Andrea PatriarcaConsulting or Advisory Role: Sanofi, SOBISpeakers' Bureau: Novartis Italy, Incyte Aspasia StamatoullasConsulting or Advisory Role: Pfizer, JanssenTravel, Accommodations, Expenses: Pfizer Katharina GötzeHonoraria: BMSConsulting or Advisory Role: BMS, AbbVie, Servier/PfizerResearch Funding: BMS Eric SolaryResearch Funding: Servier (Inst)Travel, Accommodations, Expenses: Novartis Uwe PlatzbeckerHonoraria: Celgene/Jazz, AbbVie, Curis, Geron, JanssenConsulting or Advisory Role: Celgene/Jazz, Novartis, BMS GmbH & Co. KGResearch Funding: Amgen (Inst), Janssen (Inst), Novartis (Inst), BerGenBio (Inst), Celgene (Inst), Chris (Inst)Patents, Royalties, Other Intellectual Property: part of a patent for a TFR-2 antibody (Rauner et al Nature Metabolics 2019)Travel, Accommodations, Expenses: Celgene Pierre FenauxHonoraria: CelgeneResearch Funding: Celgene (Inst)No other potential conflicts of interest were reported.

Purpose: A significant reduction of radiation-induced oral mucositis by systemic application of pentoxifylline has been demonstrated in a mouse tongue model. However, the underlying mechanisms remain unclear. The present study focuses on the development of local hypoxia in mouse tongue during daily fractionated irradiation and a potential modulation by pentoxifylline., Materials and Methods: Daily fractionated irradiation with 5×3Gy/week (days 0-4, 7-11) was given to the snouts of mice. Groups of 3 animals per day were sacrificed between day 0 and 14. Pentoxifylline (15mg/kg, s.c.) was administered daily from day -5 to the day before the mice were sacrificed. The expression of intrinsic hypoxia markers HIF-1α and GLUT1 in the epithelium of the lower tongue surface was analysed by immunohistochemistry in 3 animals per day; the percentage of positive epithelial cells and the staining intensity were analysed as endpoints., Results: Compared to untreated control tissue, fractionated irradiation resulted in a progressive increase in the expression of both hypoxia markers. This effect was significantly reduced by pentoxifylline., Conclusion: An early onset of local hypoxia occurs during fractionated irradiation in mouse tongue epithelium. The effect is markedly reduced by the mucoprotective agent pentoxifylline, suggesting a mucositis-promoting role of hypoxia; this, however, deserves further investigation., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Oral mucositis is a frequent early side effect of radio(chemo)therapy of head-and-neck malignancies. The epithelial radiation response is accompanied by inflammatory reactions; their interaction with epithelial processes remains unclear. The aim of the present study was to investigate the effect of pentoxifylline (PTX) on the oral mucosal radiation response in the mouse tongue model., Materials and Methods: Irradiation comprised fractionation (5 fractions of 3 Gy/week) over 1 (days 0-4) or 2 weeks (days 0-4, 7-11), followed by graded local top-up doses (day 7/14), in order to generate complete dose-effect curves. PTX (15 mg/kg subcutaneously) was applied once daily over varying time intervals. Ulceration of mouse tongue epithelium, corresponding to confluent mucositis, was analyzed as the clinically relevant endpoint., Results: With fractionated irradiation over 1 week, PTX administration significantly reduced the incidence of mucosal reactions when initiated before (day-5) the onset of fractionation; a trend was observed for start of PTX treatment on day 0. Similarly, PTX treatment combined with 2 weeks of fractionation had a significant effect on ulcer incidence in all but one experiment. This clearly illustrates the potential of PTX to ameliorate oral mucositis during daily fractionated irradiation., Conclusion: PTX resulted in a significant reduction of oral mucositis during fractionated irradiation, which may be attributed to stimulation of mucosal repopulation processes. The biological basis of this effect, however, needs to be clarified in further, detailed mechanistic studies.