Role of clinical markers of inflammation in assessing chronic graft versus host disease activity and severity

Desnica, Lana (2016) Role of clinical markers of inflammation in assessing chronic graft versus host disease activity and severity. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Chronic graft versus host disease (cGVHD) remains the major cause of non-relapse morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Currently there are no accepted measures of cGVHD activity to aid in clinical management and disease staging. We performed this study in a cohort of cGVHD patients highly enriched for those with established, severe and previously heavily treated disease. All patients were evaluated, and at a single time-point in their disease trajectory, the sera samples were well-annotated using a multidimensional battery of cGVHD descriptors. We analyzed clinical markers of inflammation in the sera of patients with established cGVHD and correlated those with definitions of disease activity. 189 adult patients with cGVHD (33% moderate and 66% severe according to NIH global scoring) were consecutively enrolled into a cross-sectional prospective cGVHD natural history study. At the time of evaluation, 80% were receiving systemic immunosuppression and failed a median of 4 prior systemic therapies for their cGVHD. This study identified a number of laboratory indicators of inflammation differing between patients with primarily established, moderate, or severe cGVHD and non-cGVHD transplanted controls, suggesting ongoing tissue inflammation in the patient cohort. We also identified several laboratory markers associated with the clinician's assessment of disease activity or severity. Lower albumin (p<0.0001), higher CRP (C-reactive protein; p=0.043), higher platelets (p=0.030) and higher number of PST (p<0.0001) were associated with active disease defined as clinician's intention to intensify or alter systemic therapy due to the lack of response. Higher platelet count (p=0.021) and higher number of PST (p<0.0001) were associated with more severe disease as defined by NIH global score. In the Cox proportional hazards model, better Karnofsky performance status (>= 80; p=0.0008; Hazard ratio=0.33; 95 CI: 0.17-0.63), higher FEV1 (>57; p=0.0028; Hazard ratio=0.35; 95% CI: 0.18-0.70) and higher absolute lymphocyte count (>0.65; p=0.017; Hazard ratio=0.43 (95% CI: 0.22-0.86) were associated with better survival. We developed a prognostic model and prediction equations for active and severe disease. Using this model (Table 10.), the equation for predicting disease activity was established. Based on this model, 71% of patients with active disease and 79 % of those with non-active disease would be correctly classified. Also, the equation for predicting disease severity was made and based on the developed equation, 76% of patients with severe disease and 74% of those with moderate disease would be correctly classified. This study identified common laboratory indicators of inflammation that can serve as markers of cGVHD activity and severity.

Abstract in Croatian

Kronična reakcija davatelja protiv primatelja (cGVHD) ostaje glavni uzrok morbiditeta koji nije povezan s relapsom i mortaliteta nakon transplantacije alogeničnih krvotvornih matičnih stanica. Trenutno ne postoje prihvaćene mjere cGVHD aktivnosti koje pomažu u kliničkom upravljanju i stupnjevanju bolesti. Istraživanje je provedeno na kohorti bolesnika s cGVHDom koja je uključivala velik broj onih s utvrđenom bolesti, ozbiljnim stupnjem bolesti te onih kod kojih je bolest prethodno višestruko liječena. Svi su bolesnici evaluirani te su u jednoj točki tijeka bolesti uzorci seruma temeljito opisani nizom multidimenzionalnih deskriptora cGVHD-a. Analizirani su klinički markeri upale u serumima bolesnika s utvrđenim cGVHDom i korelirali ih s definicijama aktivnosti bolesti. 189 odraslih bolesnika sa cGVHD-om (33% umjereni i 66% teški oblik prema NIH globalnom skoringu) je konsekutivno upisano u cross-sectional prospektivno istraživanje prirodnog tijeka cGVHD-a. U vrijeme evaluacije, 80% je primalo sistemsku imunosupresiju te je medijan neuspješnih prethodnih sistemskih terapija za cGVHD bio 4. Ova je studija identificirala niz laboratorijskih pokazatelja upale koji se razlikuju među bolesnicima s primarno utvrđenim, umjerenim i teškim oblikom cGVHD-a i bolesnicima koji su transplantirani no nemaju cGVHD, što sugerira aktivnu upalu tkiva u kohorti bolesnika. Također smo identificirali nekoliko laboratorijskih markera povezanih s procjenom aktivnosti ili težine bolesti koju donosi kliničar. Niži albumin (p<0.0001), viši CRP (C-reaktivni protein; p=0.043), viši trombociti (p=0.030) i više vrijednosti PST-a (p<0.0001) povezani su s aktivnom bolešću koja se definira kao namjera kliničara da intenzivira ili mijenja sistemsku terapiju zbog nedostatka odgovora. Veći broj trombocita (p=0.021) i veća razina PST-a (p<0.0001) povezani su s težim oblikom bolesti prema NIH globalnom skoringu. U Coxovom regresijskom modelu, bolji Karnofskyjevom skalom izvedbenog statusa (Karnofsky Performance Status) (>= 80; p=0.0008; Omjer hazarda=0.33; 95 CI: 0.17-0.63), veći FEV1 (>57; p=0.0028; Omjer hazarda =0.35; 95% CI: 0.18-0.70) i viša apsolutna vrijednost limfocita (>0.65; p=0.017; Omjer hazarda=0.43 (95% CI: 0.22-0.86) su povezani s boljim preživljenjem. Razvijen je prognostički model i jednadžbe za predikciju za aktivne i teške oblike bolesti. Koristeći se ovim modelom (Tablica 10), utvrđena je jednadžba za predviđanje aktivnosti bolesti. Na temelju tog modela, pravilno je klasificirano da 71% bolesnika ima aktivnu bolest, a 79% neaktivnu bolest. Također je izrađena i jednadžba za predviđanje težine bolesti, na temelju koje je pravilno klasificirano da 76% bolesnika ima težak oblik bolesti, a 74% umjereni oblik bolesti. Ovim su istraživanjem identificirani laboratorijski pokazatelji upale koji mogu služiti kao markeri za aktivnost i težinu cGVHD-a.

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