Fluid Overload As New Toxicity Category Has a Strong Impact on Non Relapse Mortality and Survival in Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Rondon Gabriela , Saliba Rima M , Chen Julianne , Ledesma Celina , Alousi Amin M. , Oran Betul , Hosing Chitra M. , Kebriaei Partow , Khouri Issa F. , Shpall Elizabeth J. , Popat Uday R. , Champlin Richard E. , Ciurea Stefan O. 
Published: October 2019

Abstract
Background: Fluid retention/overload (FO) is common during hospitalization for allogeneic stem cell transplantation (ASCT) and is associated with weight gain (WG), edema, and other symptoms such as shortness of breath. It is unknown if symptomatic FO impacts transplant outcomes. We hypothesized that FO is associated with non-relapse mortality (NRM) and worse survival after ASCT.
Methods: FO was scored by an independent team using the following criteria: grade 1 - asymptomatic weight gain <10% from baseline requiring occasional diuretics; grade 2 -symptomatic and or WG 10%-20% from baseline requiring continuing diuretics grade 3 WG ≥20% from baseline requiring further treatment (dialysis) with or without renal, pulmonary, and or cardiac dysfunction; grade 4 - major organ dysfunction.
Results: We initially evaluated FO in a cohort of haploidentical transplant patients with hematologic malignancies (N=145) all treated with identical conditioning (melphalan-based) regimen, and received predominantly a bone marrow graft (94%). The median follow-up was 18 months. 43% of patients were in CR1/2. Median age for this group was 45 years (range 19-69), 58% were males. Median weight was 82 kg (37-180kgs) at study entry before starting the preparative regimen. The median creatinine was 0.75 with >1.0 mg/dl in 16% of the patients. Median DLCO was 70 and EF was normal (>40%) in all except 2 patients. Thirty patients (21%) developed ≥ grade 2 FO. Factors associated with Day100 NRM were ≥ grade 2 FO (HR 15, CI 4.2-55, p<0.001), cr>1 (HR 4.7, CI 1.6-14, p=0.005) and age>55 (HR 4.5, CI 1.5-13, p=0.008) by univariate analysis. In multivariate analysis (MVA) factors that retained significance were FO ≥ grade 2 (HR 13.1, CI 3.4-50, p<0.001) and cr>1 at study entry (HR 3.5, CI 1.1-11, p=0.03).
We verified the prognostic value of FO in a separate cohort of HLA matched transplants [N= 449, 190 matched related donor (MRD) and 259 matched unrelated donor (MUD)] with AML/MDS treated with fludarabine and busulfan conditioning. The median follow-up for this group was 23 months. The median age was 58 years (range 18-77). 42% were in CR1/2 at transplant. 68% had a peripheral blood graft. Median weight was 81kg (47-170). Median creatinine at transplant was 0.8, 19% had >1 mg/dl. Median DLCO was 71 and EF was normal (>40%) in all except 2 patients. Significant factors associated with Day100 NRM by univariate analysis, were FO ≥ grade 2 (HR 11, CI 4.5-25, p<0.001) and advanced disease status at transplant (not in CR1/2) (HR 3.5, CI 1.2-10, p=0.02). By MVA, FO≥ grade 2 was the only factor highly associated with Day100 NRM (HR 34, CI 7.2-158, p<0.001), and advanced disease status in patients with FO<2 (HR 5, CI 1.1-22, p=0.03). Worse NRM translated in significantly worse 3-years survival for patients with FO in both haploidentical and HLA matched transplants group (Figure). Haploidentical transplant patients with FO≥2 were more likely to have weight < 80 kgs(57% vs.33%, p=0.02), but there was no such correlation in the matched transplants group.
Conclusions: FO should be considered an important adverse event post ASCT. Grade 2 or greater FO is strongly associated with NRM and worse survival. FO is likely related to the rate of intravenous fluid administration and other factors (oncotic pressure, capillary leak and major organ dysfunction post-transplant). Caution is warranted to prevent excessive hydration and weight gain in the early post-transplant period. Other factors potentially associated with weight gain will be evaluated.
Figure 1. (A) NRM and (B) OS in haploidenticaltransplants; (C) NRM and (D) OS in matched transplants. Figure 1. (A) NRM and (B) OS in haploidenticaltransplants; (C) NRM and (D) OS in matched transplants.

Disclosures
Alousi: Therakos, Inc: Research Funding.