Nicotinamide (vitamin B3) treatment improves response to G?CSF in severe congenital neutropenia patients

Severe congenital neutropenia (CN) is an inherited bone marrow failure syndrome with markedly reduced granulocyte number and function that often manifests life-threatening bacterial infections.1 Granulocyte colony-stimulating factor (G-CSF) treatment the primary therapeutic approach aimed at keeping levels or above 1 000/µl to prevent infectious complications.2 Some CN patients require high doses of G-CSF reach this goal, a small group not responsive therapy all. Overall cumulative 15-year incidence death from sepsis for was described be as 10%.3 There also some evidence risk development acute myeloid leukaemia (AML) myelodysplastic (MDS) higher in who G-CSF.3, 4 The association dose relative hazard MDS/AML detected.3 Therefore, other options may lead reduction increase functions are required. We recently demonstrated nicotinamide (NA, vitamin B3) acts through NAD+/SIRT1 protein deacetylation pathway, leading upregulating expression receptors.5 When we treated healthy volunteers 20 mg/kg/day Jenapharm, Jena, Germany) daily, they showed marked neutrophilic numbers.5 evaluate whether NA will neutrophil numbers required dose. For this, were orally addition therapy. After three months treatment, absolute peripheral blood neutrophils, monocytes, eosinophils, thrombocytes, lymphocytes, well haemoglobin, evaluated. In patients, counts evaluated after one year on Eighteen included study: 15 cyclic (CyN) (Table I). study 11 males seven females ages 0·5 31 years [median 5·5 years; first quartile (Q1) 3·6, third (Q3) 8·5]. diagnosis CyN made based Chronic Neutropenia International Registry (SCNIR) diagnostic criteria.1 Fourteen harboured mutations ELANE, two had X-linked harbouring WAS mutations, no genetic defect has been detected yet. Two ELANE patient despite clear cycling All received between 0·6 50·8 µg/kg/day before initiation local ethic committees approved protocol, and\or their parents gave informed consent participate study. Analysis revealed gradual (ANC) 14 18 (78%). them completely replaced by combined (including mono-NA therapy), median ANC 0·95 × 109/l (Q1 0·64, Q3 1·51) combination 1·80 1·50, 2·73) (Fig 1A, B), 0·76 1·4l; P < 0·001). No statistically significant differences cell subsample 16 whom complete available 1C). nine out (50%), led ANCs including replacement patient. Thus, 13·3 4·4, 23·8) 8·6 1·6, 15·1) decrease 0·8 0, 3·3; = 0·007; Fig 1D). beneficial effect observed most during continuous treatment; lost follow-up. observations, 1·66 1·00, 2·85), since start 0·85 0·08, 1·57; 0·004). well-tolerated long-term option, without severe adverse events. Four have currently more than five six exhaustion responses NA. During time combinatorial G-CSF, transplantation due acquisition monosomy 7 (pt. # 5 years, pt. #7 1·5 12 treatment). these (Cys151Ser Gly214Arg #12) associated AML MDS.6 Morphological analysis remaining obvious morphology (data shown). frequency severity infections. As example, (#7) up 50 achieve 000/µl. Upon NA, 3 achieved further increases (three months) patient, able 12·5 µg/kg/day, good clinical laboratory results (Figure S1A). (#18), monotherapy even sufficient infections, cycling. This years. Another (#2) episodes profound absent neutrophils unresponsiveness which he developed multiple nadir his level increased 0·40 109/l, Taken together, our responses. use promising should investigated larger cohort patients. It would interesting investigate types acquired respond Particularly, implementation chemotherapy-induced shorten neutropenic phases, improving chemotherapy regimens. important decreasing G-CSFR leukaemias. therapy, 7. These data suggest leukaemogenic transformation. However, protects leukaemia-associated CSF3R and/or RUNX1 prevents leukaemogenesis observation Also, NA-treated strengthen infections upon work supported BMBF (JS, KW). authors relevant conflicts interest disclose. Please note: publisher responsible content functionality any supporting information supplied authors. Any queries (other missing content) directed corresponding author article.