Non-Relapse Mortality in Chronic Graft Versus Host Disease: Risk Factors At Onset and Reponse to Treatment

Chronic graft versus host disease (cGVHD) is a major contributor to morbidity and mortality in long-term survivors of allogeneic hematopoietic cell transplantation (HCT). The treatment course is heterogeneous and unpredictable, and a prognostic system at the time of disease onset is highly desirable. We developed a simple system that should minimize inter-provider variability, and can be applied at disease onset.  We studied 341 consecutive adult patients (age 18-71y; median 53y) who received HCT at the University of Michigan from 2007 to 2010.  Data was prospectively collected under an IRB approved protocol.  Cumulative incidence of cGVHD was 47%, with a median time to onset of 190d (range 37-806d). We performed univariable analysis on multiple potential risk factors (RF) for non-relapse mortality (NRM), with relapse as a competing risk (Table).   History of severe acute GVHD grades III/IV (severe aGVHD) (Hazard Ratio (HR)=4.0, p<0.001), Karnofsky performance score (KPS) ≤ 70% (HR 4.6, p<0.001), and grade 2/3 lung (HR=3.3, p=0.04) were the strongest predictors of NRM, while presence of grade 1 liver cGVHD was protective (HR=0.3, p=0.03).  The simplest stratification grouped patients into 3 categories:  High risk (KPS ≤ 70% and/or severe aGVHD), low risk (grade 1 liver, without high risk features), and intermediate risk (all others).  Four year NRM in our model was 52% in high risk (n=44, ref), 4% in low risk (n=28, p=0.01), and 18% in intermediate patients (n=86, p=0.001). Within the high risk group, both low KPS and prior severe aGVHD remained independent predictors after adjustment for each other (HR=4.5, p=0.02 and HR=3.4, p=0.02, respectively), and in the entire cohort. Low KPS patients were more likely to have lung involvement, be on steroids, and have more severe cGVHD, implying that KPS serves as a composite of multiple other RF, including both HCT-related morbidities and cGVHD burden. In addition to KPS and history of severe acute GVHD, lack of response 1 month after the initiation of therapy was independently predictive of NRM in 141 treated patients (HR= 3.1, 95% CI 1.3-7.4, p<0.01).   If validated in an independent population, this classification system may be clinically useful and facilitate referral and management in chronic GVHD clinics.

	Univariable
Risk Factor	n	HR	95% CI	p value
Before Onset
Age at HCT, y
18-40	29	Ref
41-55	70	1.8	0.5-6.4	0.3
> 55	59	2.3	0.7-8.05	0.2
Related donor	79	0.6	0.3-1.2	0.2
Reduced Intensity Conditioning	51	1.1	0.5-2.4	0.7
History of aGVHD III-IV	20	4.0	1.9-8.5	<0.001
Onset
Karnofsky Performance Score ≤ 70%	31	4.6	2.5-9.5	<0.001
NIH Onset Severity
Mild	23	Ref
Moderate	79	0.6	0.2-1.8	0.4
Severe	56	1.2	0.4-3.4	0.7
Progressive onset vs De novo/Quiescent	34	2.1	1.0-4.5	0.05
Platelets < 100,000/mm3 at onset	42	1.4	0.7-3.1	0.3
On steroids at onset	28	2.0	0.9-4.5	0.09
NIH grade 1 liver at onset	40	0.3	0.1-0.9	0.03
NIH grade 2/3 lung at onset	17	3.3	1.03-10.3	0.04