Assessing the Validity of the NIH Response Criteria for Chronic Graft-Versus-Host Disease (cGVHD): Consensus Measures Correlate with Clinical Outcomes,

Lack of standardized criteria for measuring therapeutic response remains a significant obstacle to the evaluation of new cGVHD treatments. In 2005 an NIH consensus conference proposed a set of organ-specific measures for quantification of change after a therapeutic intervention (BBMT 2006, 12:252). We conducted a cross-sectional prospective study to validate the NIH response criteria by analyzing the correlations between proposed clinician (Form A) or patient reported (Form B) scales and the set of established clinically important outcomes: NIH global severity, average NIH organ score, sub-specialist evaluations (SSE), disease activity by therapeutic intent, Lee symptom scale, SF-36 (PCS, MCS), HAP score (MAS, AAS) and overall survival (OS). Patients and Methods: 193 adults, age 48 years, (18–70) were enrolled from 2004–2011 on the NCI cGVHD natural history protocol at a median of 36 months (4–258) from transplant. Patients received a median of 4 (0–9) prior systemic therapies, and 83% were on systemic immunosuppression, 67% had severe, 30% had moderate and 3% had mild NIH global score. Median number of involved organs was 5 (1–8). NIH response criteria measures were obtained at the time of study entry. Univariate and multivariate logistic regression analysis were undertaken to determine correlations between response criteria items and outcomes. Results: The median values of the NIH response criteria items were: Clinician reported – Skin %BSA (erythema 0.9 [0–80], moveable sclerosis 0.54 [0–81], non-moveable sclerosis 0 [0–76]), Schirmer 1 tear test (mm) 3 [0–29.5], oral scale 1 [0–12], WBC 7.1 [1.96–31.3], AST 32 [5–256], bilirubin 0.5 [0.1–1.7], gastrointestinal (upper 0 [0–3], esophageal 0 [0–3], lower, 0 [0–3]), lung function score (LFS) 4 [0–12], health care provider global rating (HCP) 2 [0–3], clinician rated symptom severity 6 [0–10], clinician evaluation of change 0 [-3-+3], grip strength (psi) 66 [1–138], walk time (feet/min) 109 [40–145], Karnofsky score (KPS) 80 [30–100]. Patient reported - symptoms intensity (skin itching 2 [0–10], mouth dryness 2 [0–10] pain 0 [0–10] or sensitivity 1 [0–10], eyes 5 [0–10], patient global score 2 [1–3], patient rated symptom severity 5 [0–10], patient evaluation of change 0 [-3-+3]. Most of the elements had statistically significant association with clinical outcomes in univariate analyses. Multivariable analyses demonstrated associations between response criteria items and outcomes (Table 1). Schirmer tear test, oral score, WBC, AST, lower GI symptoms, grip strength, skin itching intensity and clinician or patient evaluation of cGVHD change did not show significant associations with any of the outcomes. 3-year survival for the cohort is 75%. Median follow-up of surviving patients was 33 months. Factors associated with OS included: BSA% erythema (p=0.0018), LFS (p=0.014), walk velocity (p=0.018), KPS (p<0.0001), and mouth pain (p=0.03). In the Cox proportional hazards model higher BSA% erythema (>3.0%, p=0.0126; HR=2.5; 95 CI: 1.2–5.1), higher LFS (>=8, p=0.0218; HR 2.3, 95 CI: 1.1–4.8) and lower KPS (30–70%, p=0.02; HR=2.3; 95 CI: 1.1–4.7) predicted lower OS. Conclusions: A number of response criteria measures proposed by the NIH cGVHD consensus project predict important clinical outcomes. These results thus identify a subset of measures that may serve as surrogate endpoints and should be prioritized for further evaluation in clinical studies.

No relevant conflicts of interest to declare.