Pre-Transplant Ferritin, Albumin and Platelet Count Add Prognostic Information to Comorbidities for Allogeneic Hematopoietic Cell Transplantation (HCT) Outcomes: A Multi-Center Discovery-Validation Study
Authors: Vaughn Jennifer E. , Storer Barry E. , Armand Philippe , Raimondi Roberto , Gibson Christopher J , Rambaldi Alessandro , Ciceri Fabio , Oneto Rosi , Bruno Benedetto , Martin Paul J. , Sandmaier Brenda M. , Storb Rainer F. , Sorror Mohamed L. 
Published: November 2019

Abstract

Albumin, ferritin, and peripheral blood counts broadly capture health status in patients undergoing allogeneic stem cell transplantation (HCT). Whether they add any prognostic information to the HCT-Comorbidity Index (HCT-CI) is unknown. We analyzed the independent prognostic role of a group of 5 biomarkers (ferritin, albumin, absolute neutrophil count (ANC), hemoglobin (Hgb), and platelet (Plt) count) in pts given allogeneic HCT for hematologic malignancies.
This was a multi-center, retrospective discovery-validation study comprising data from 3917 recipients of allogeneic HCT at the Fred Hutchinson Cancer Research Institute (FHCRC) (n=1789) and Dana Farber Cancer Institute (DF) (n=716) in the US and the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) (n=1412) in Italy (Table 1). Proportional hazard models were used to estimate the hazards of non-relapse mortality (NRM) and survival after adjustment for the HCT-CI, donor type, CMV serostatus, regimen intensity, age, disease risk and Karnofsky Performance Status (KPS). These were stratified by institution. Model performances were tested by c-statistic estimates.
In an initial analysis within the FHCRC population, ANC of <500 and Hgb of < 9 were not associated with outcomes in the models. Alternatively, ferritin >1000 (HR 1.98; p=0.0003) and >2500 (HR 1.97; p=0.0005); albumin <3.5 (HR 1.63; p<0.00001) and <3.0 (HR 1.73 p<0.0001); and Plt <100k (HR 1.65; p<0.0001), <50k (HR 1.52; p<0.0001) , and <20K (HR 1.54; p<0.008) were all statistically significantly associated with NRM.
Results were validated in a larger population from DF and GITMO. In multivariate models, adjusted for previously mentioned variables, ferritin >2500 and incremental decreases in albumin and Plt counts had statistically significant associations with both NRM and survival (Table 2). Of note, HCT-CI scores (2, 3 and >4) also retained significant associations with NRM and survival in the presence of the three biomarker values and in both cohorts. Subsequent multivariate analyses stratified the whole cohort (n=3917) into a training (n=2352) and a validation (n=1407) set. In both sets, albumin <3.5, plts <100K, and ferritin >2500 had statistical significance associations with NRM and survival. Each of the three biomarker values were subsequently assigned a weight of 1 following the same equation used to develop the HCT-CI. The augmented HCT-CI/biomarker index had higher c-statistic estimate (0.61) for prediction of NRM compared to the HCT-CI alone (0.58) in the validation set.
Ferritin, albumin, and Plt counts are simple and valid prognostic biomarkers for transplant outcomes and should be considered in combination with the HCT-CI in risk assessment prior to allogeneic HCT. The physiology behind these associations warrants further investigation to identify areas of intervention that may improve outcomes.
Table 1: Pt characteristics FHCRC(N=1789) DF/GITMO(N=2128) N (%) N (%) Donor Related 900 (50) 1062 (50) Unrelated 889 (50) 1053 (50) Disease risk Low 740 (41) 866 (43) High 1049 (59) 1157 (57) Age < 50 1025 (57) 1120 (53) ≥ 50 764 (43) 1008 (47) Conditioning MA 983 (55) 1100 (52) RIC/NMA 806 (45) 1004 (48) Pt CMV - 773 (43) 505 (24) + 1016 (57) 1581 (76) KPS ≤ 90 691 (39) 644 (33) 90-100 1098 (61) 1304 (67)
Table 2: Multivariate analysis showing the associations between biomarkers and NRM and survival. NRM Survival Marker HR1 P1 HR1 P1 FHCRC Albumin ≥3.5 1.0 1.0 <3.5 - 3.0 1.44 0.002 1.45 <0.0001 <3.0 1.77 <0.0001 1.77 <0.0001 Unk 1.15 0.38 1.19 0.11 Plts ≥100K 1.0 1.0 <100K – 50K 1.48 0.0007 1.28 0.003 <50K – 20K 1.49 0.003 1.37 0.001 <20K 1.64 0.005 1.58 0.0004 Unk 0.66 0.47 0.48 0.14 Ferritin ≤1000 1.0 1.0 >1000 - 2500 1.60 0.03 1.70 0.0006 >2500 2.08 0.001 1.63 0.007 Unk 1.42 0.03 1.44 0.002 HCT-CI 0 1.0 1.0 1 1.29 0.12 1.31 0.02 2 1.50 0.01 1.42 0.001 3 2.29 <0.0001 2.04 <0.0001 ≥ 4 2.94 <0.0001 2.42 <0.0001 DF/GITMO Albumin ≥3.5 1.0 1.0 <3.5 - 3.0 1.60 0.0001 1.36 0.0005 <3.0 2.77 <0.0001 2.18 <0.0001 Unk 1.61 0.01 1.11 0.49 Plts ≥100K 1.0 1.0 <100K – 50K 1.08 0.56 1.02 0.85 <50K – 20K 1.17 0.28 1.21 0.06 <20K 1.38 0.04 1.35 0.009 Unk 0.64 0.10 0.82 0.28 Ferritin ≤1000 1.0 1.0 >1000 - 2500 1.11 0.43 1.23 0.02 >2500 1.60 0.002 1.69 <0.0001 Unk 1.13 0.33 1.12 0.19 HCT-CI 0 1.0 1.0 1 1.31 0.05 1.14 0.19 2 1.29 0.10 1.25 0.04 3 1.48 0.006 1.46 0.0001 ≥ 4 1.74 <0.0001 1.66 <0.0001 1 Adjusted for donor , CMV serostatus , regimen intensity , age , disease risk , KPS ; stratified on institution. Unk=Unknown

Disclosures
No relevant conflicts of interest to declare.