Table 3.

Summary of studies reporting results on functional capacity tests or self-reports of functional capacity and physical domain of quality of life (QoL) in patients with chronic graft versus host disease (cGVHD).

Reference	N, age (average) and gender (%)	cGVHD onset (%)	NIH cGVHD global severity (%)	cGVHD NIH subtype (%)	Source of transplant (%)	Functional capacity tests	Self-reports of functional capacity or physical domain of QoL	Main results
(15)	N=427 With classic Median age in years (range): 49 (17–69) 99% adults M=64; F=36 With overlap Median age in years (range): 51 (2–79) 96% adults M=57; F=43	-	None: 0.47 Mild: 10 Moderate: 57.2 Severe: 32.3 With classic None: 3 Mild: 9 Moderate: 63 Severe: 25 With overlap Mild: 10 Moderate: 56 Severe: 34	Classic: 18 Overlap: 82	Bone marrow: 7.54 PBSC: 87.6 UC: 4.94 With classic Bone marrow: 5 PBSC: 90 UC: 5 With overlap Bone marrow: 8 PBSC: 87 UC: 5	2-MWT HGS test PFTs (and portable spirometry)	HAP SF-36 FACT-BMT L-cGVHD-SC	-Patients with overlap syndrome had lower values in 2-MWT, FEV1, SF-36 social functioning scores, HAP, and higher symptom burden than patients with classic cGVHD. -The overlap cGVHD was associated with worse overall survival (HR 2.1, 95% CI 1.1–4.7; p=0.03) and higher non-relapse mortality (HR 2.8, 95% CI 1.2–8.3; p=0.02) than classic cGVHD.
(50)	With cGVHD N=117 Median age in years (range): 44 (21–72) M=55.6; F=44.4 Without cGVHD N=59 Median age in years (range): 44 (18–67) M=45.8; F=54.2	Unknown: ? De novo ? Progressive: 20,5 Quiescent: ?	Mild: 28.3 Moderate: 42.7 Severe: 29	Classic: 100	Allo-HSCT: 100	-	HAP SF-36 FACT-BMT L-cGVHD-SC	-The HAP MAS and AAS correlated inversely with cGVHD severity (r=−0.25 for MAS and −0.24 for AAS). -Lung manifestations of cGVHD correlated with AAS (r=0.17), but not with MAS. -HAP scores correlated with subscales from other instruments measuring physical domains, especially the PCS SF-36. -There were high internal consistency of HAP and good correlation of MAS and AAS with cGVHD severity. -The HAP had higher sensitivity to change of cGVHD activity compared to the SF-36 and the FACT-BMT. -Steroid myopathy correlated with both HAP scores.
(53)	N=189 Average age in years (range): 48 (18–70). M=52; F=48	Unknown: 0.5 De novo 35.5 Progressive: 42 Quiescent: 22	Mild: 1 Moderate: 33 Severe: 66	Classic: 88 Overlap: 12	Bone marrow: 18.5 PBSC: 81 UC: 0.5	2-MWT HGS test PFTs ROM	HAP SF-36 FACT-BMT L-cGVHD-SC	-NIH global severity scores were associated (p≤0.001 to p≤0.05) with all measures, with the exception of SF-36 MCS. -Joints/fascia, skin, and lung scores showed highest number of significant associations with almost all outcome measures, having a big impact on function and QoL. -Joints/fascia and skin scores, but not lung, were associated with intensity of immunosuppression (both p<0.0001), therapeutic intent at the time of evaluation (p<0.0001 for both), and clinician 7-point global assessment of change (p<0.0001 for both). -The L-cGVHD-SC was correlated with gastrointestinal score and a NIH Global Score of “severe”. -NIH lung score of 3 versus <3 was the most strongly negatively associated with survival, with a 3-year estimated survival of 35% versus 82% respectively, p<0.0001.
(61)	N=100 Median age in years (range): 46 (20–66) M=52; F=48	Unknown: 0 De novo 40 Progressive: 43 Quiescent: 17	Mild: 5 Moderate: 45 Severe: 50	-	Bone marrow: 18 PBSC: 80 Unspecified: 2	2-MWT HGS test ROM	SF-36 L-cGVHD-SC	-The mean PCS and seven of eight SF-36 subscale scores were significantly lower (mean=36.8±10.7) than the US population norm of 50 (p<0.001). -The highest decrements were in physical function (mean=38.8±10.9) and physical role function (mean=37.8±11.8). -Significant independent predictors of impaired performance were intensive systemic immunosuppression, reduced capacity for ambulation, and greater cGVHD symptom bother (p<0.05). -Symptom bother had a direct effect on functional performance, as well as an indirect effect partially mediated by functional capacity (Sobel test, p=0.004).
(63)	N=264 Median age in years (range): 36.1±11.1 M: 63.3; F: 36.7	De novo 62.1 Progressive: 3.4 Quiescent: 34.5	Mild: 28.4 Moderate: 52.3 Severe: 19.3	Classic: 69.3 Overlap: 30.7	Allo-HSCT:100	-	SF-36	-Patients with mild cGVHD had better QoL than in those with moderate cGVHD (p<0.05). -Patients with mild or moderate cGVHD had better QoL than in those with severe cGVHD (p<0.01). -Chronic GVHD severity had the greatest significant negative impact on patients’ QoL (PCS: OR=1.4; 95% CI: 1.1–1.8; p=0.004; MCS: OR=1.6; 95% CI, 1.1–2.1; p=0.005), whereas being female was associated with a negative impact on the MCS (OR=1.6; 95% CI: 1.0–2.4; p=0.039).
(64)	N=336 Median age in years (range): 52 (19–79) M: 60; F: 40	-	Change in cGVHD severity was examined by comparing severity at each visit to severity at the previous visit.	Classic: 77 Overlap: 23	Allo-HSCT: 100	-	SF-36 FACT-BMT FACT-G	-Change in NIH-assessed global cGVHD severity over a 6-month average timeframe was not associated with change in QoL. -Changes in clinician-assessed cGVHD were associated with changes in the FACT-G and FACT-BMT scores. -Change in patient-reported cGVHD severity was correlated with change in both the SF-36 and FACT-BMT. -Patients demonstrated clinically relevant improvement or worsening in QoL compared to that at the prior visit in approximately 40% of follow-up visits. -The SF-36 and FACT-BMT perform well in capturing thepatients’ perspective, and fairly well in capturing physicians’ assessment. Neither correlates well with changes in NIH global severity scores.
(65)	N=298 → 87% completed all or part of the SF-36 and FACT-BMT Median age in years (range): 53 (20–79). M=58; F=42	-	Mild: 10 Moderate: 59 Severe: 31	Classic: 56 Overlap: 44	Bone marrow: 11 PBSC: 89	-	SF-36 FACT-BMT	-Chronic GVHD severity was independently associated with QoL, adjusting for age. -Significant differences were found most often between average QoL scores in moderate and severe cGVHD patients, with fewer significant differences between mild and moderate GVHD. -QoL composite and subscale scores were higher on average for patients with moderate GVHD compared with severe cGVHD. Differences in QoL between mild and severe cGVHD were of greater magnitude than between moderate and severe. -Mean scores for cGVHD patients were significantly lower for physical functioning, role-physical, bodily pain, general health, vitality, social functioning, and PCS than population normative data.
(70)	N=522 Adolescent and young adult (AYA) 18–40 years =22% M=49; F=51 Middle-aged: 41–59 years =53% M=57; F=43 Older: ≥60years =25% M=63; F=37	-	Moderate: 58 Severe: 42 AYA Moderate: 55 Severe: 45 Middle-aged Moderate: 59 Severe: 41 Older Moderate: 58 Severe: 42	-	AYA Bone marrow: 19 PBSC: 77 UC: 4 Middle-aged Bone marrow: 5 PBSC: 92 UC: 4 Older Bone marrow: 2 PBSC: 94 UC: 4	2-MWT	HAP SF-36 FACT-BMT L-cGVHD-SC	-Older patients had lower psychological symptom burden and lower functional status compared to AYA and middle-aged patients. -HAP scores were significantly lower for older patients compared to AYA and middle-aged patients (p<0.001). -FACT-BMT scores were higher for older patients compared to middle-aged patients, and similar to AYA patients. -Older and AYA had comparable FACT-BMT scores, which were higher than middle-aged patients scores. -Older patients reported lower SF-36 PFS scores compared to AYA and middle-aged patients, but less bodily pain (p=0.007).
(71)	N=567 Median age in years (range): 51 (2–79). 98% adults. M: 57; F: 43	-	Mild: 9 Moderate: 52 Severe: 39	-	Bone marrow: 7 PBSC: 89 UC: 4	2-MWT HGS test	HAP SF-36 FACT-G L-cGVHD-SC	-Lower gastrointestinal involvement (HR 1.67, p=0.05) and elevated bilirubin (HR 2.46, p=0.001) were associated with overall survival; both were also associated with non-relapse mortality. In multivariable analysis using all visits, gastrointestinal score greater than zero (HR 1.69, p=0.02) and elevated bilirubin (HR 3.73, p<0.001) were associated with overall survival; results were similar for non-relapse mortality. -Any esophageal involvement and gastrointestinal score greater than zero were associated with both symptoms and QoL. Elevated bilirubin was associated with QoL. -Upper gastrointestinal involvement was associated with an estimated of 31.7 feet less (p<0.001), and overall liver involvement was associated with an estimated of 19.4 feet less (p=0.001) achieved in the 2-MWT. Upper gastrointestinal was associated with HGS test (p=0.04).
(81)	N=584 Median age in years (range): 51.5 (2–79) 98% adults M=58; F=42	-	None: 1 Mild: 8 Moderate: 52 Severe: 39	-	Bone marrow: 7 PBSC: 88 UC: 5	2-MWT HGS test	HAP SF-36 FACT-BMT L-cGVHD-SC	-The 2-MWT was significantly associated with domains of the L-cGVHD-SC (overall, skin, lung, energy), SF-36 domain and summary scores, FACT summary and domain scores, and HAP scores (all p<0.001). -The 2-MWT and HGS both had significant association with global cGVHD severity. -Impaired performance in the 2-MWT was associated with higher odds of gastrointestinal, liver, and lung involvement. -Two-MWT was significantly associated with overall survival, non-relapse mortality, and failure-free survival, while no association was found for HGS test.
(84)	N=567** Present: N=164 Median age in years (range): 52 (42–58) M=57; F=43 Absent: N=403 Median age in years (range): 51 (42–60) M=58; F=42	-	Present: Mild: 2 Moderate: 50 Severe: 48 Absent: Mild: 12 Moderate: 53 Severe: 35	-	Present: Bone marrow: 6 PBSC: 89 UC: 5 Absent: Bone marrow: 7 PBSC: 89 UC: 4	2-MWT HGS test ROM (NIH joint/fascia scale) P-ROM	HAP SF-36 FACT-G L-cGVHD-SC	-There was a 29% incidence of joint/fascia manifestations in patients with cGVHD. -P-ROM scale was the most sensitive to perceived joint worsening among all scales. -The Lee muscle/joint symptom subscale was useful for capturing changes in joint-specific symptoms -The L-cGVHD-SC was useful for capturing changes in overall symptoms. -The FACT-G was sensitive to worsening but not to improvement, while the converse was true of the SF-36 PCS. -Joint improvement was evident by 3 months after the onset of joint/fascia manifestations, and these patients experienced worsening in ROM within 6 months if joint/fascia manifestations developed >3 months after diagnosis of cGVHD.
(85)	N=9 Median age in years (range): 47 (13–53) M=67; F=33	-	Mild: 11 Moderate: 22 Severe: 67	Classic: 67 Overlap: 33	Bone marrow: 55 PBSC: 45	2-MWT HGS test ROM	-	Results of this study support the need of training investigators interested in participating in cGVHD clinical trials and the need for simplifying current tools to evaluate the cutaneous involvement measurements.
(86)	N=283 Median age in years (range): 51 (2–79). M=59; F=41 Incident cases: 53%. Prevalent cases: 47%	-	Mild: 13 Moderate: 59 Severe: 28	Classic: 17 Overlap: 83	Bone marrow: 6 PBSC: 89 UC: 5	PFTs (and NIH symptom-based lung score)	HAP SF-36 FACT-BMT L-cGVHD-SC	-Complete or parcial responses at 6 months after enrollment correlated with changes in symptom burden among incident cases, but not among prevalent cases. -Response at 6 months was not associated with changes in QoL or survival outcomes in either group. -Modifications of the current response algorithm are needed to improve correlations with clinical benefits.
(87)	N=496 97% adults. 3% child. M: 58; F: 42	-	<mild: 1 Mild: 8 Moderate: 53 Severe: 38	-	Bone marrow: 7 PBSC: 88 UC: 5	PFTs (and NIH symptom-based lung score)	SF-36 FACT-BMT L-cGVHD-SC (Lee lung symptom score)	-Pulmonary dysfunction was present at enrollment in 34% of patients based on PFTs and 25% based on symptoms. -The NIH symptom-based lung score was associated with nonrelapse mortality (p=0.02), overall survival (p=0.02), patient-reported symptoms (p<0.001) and functional status (p<0.001). -Worsening of NIH symptom-based lung score over time was associated with higher nonrelapse mortality and lower survival. -NIH symptom-based lung score was correlated with the Lee lung symptom score, Lee summary symptom score, SF36-PCS, and FACT-BMT trial outcome index (all p<0.001).

All patients included were evaluated according to the National Institute of Health cGVHD staging form, with ≥70% of the patients in each study cohort having cGVHD and being predominantly adults.

Abbreviations: AAS, adjusted activity score;AYA, Adolescent and young adult;allo-HSCT, allogeneic hematopoietic cell transplantation; CI, confidence interval; F, female;FACT-BMT, Functional Assessment of Cancer Therapy of Bone Marrow Transplant; FACT-G,Functional Assessment of Cancer Therapy-General;FEV₁, forced expiratory volume in 1 second; HAP, Human Activities Profile; HGS, hand grip strength test;HR, hazard ratio; L-cGVHD-SC, Lee cGVHD Symptom Scale;M, male; MAS, maximum activity score;MCS, mental component score; NIH, National Institutes of Health;OR, odd ratio; PBSC, peripheral blood stem cells; PCS, physical component score; PFTs, pulmonary function tests; P-ROM, Photographic-ROM;ROM, range of motion; SF-36, Short Form 36; UC, umbilical cord; 2-MWT, 2-minute walk test. Definitions: Progressive onset of chronic GVHD is that following unresolved acute GVHD, quiescent onset of cGVHD is that occurring after complete resolution of acute GVHD, and de novo onset of cGVHD is that appearing in patients who have not had previous acute GVHD.

^**Characteristics of the patients grouped by presence or absence of joint/fascia manifestations at the time of enrollment.