Lee cGVHD Symptom Scale Research Articles

Development and psychometric testing of a pediatric chronic graft-versus-host disease symptom scale: protocol for a two-phase, mixed methods study.

Chronic graft-versus-host disease (cGVHD) is a debilitating late complication of hematopoietic stem cell transplantation. It is often accompanied by extensive symptom burden. No validated cGVHD patient-reported outcome (PRO) measure exists to evaluate cGVHD symptom bother in children and adolescents younger than 18 years. This paper presents the study protocol for a multi-center, two-phase protocol to develop a psychometrically valid pediatric cGVHD Symptom Scale (PCSS) and a companion caregiver-proxy measure to capture the symptom burden experienced by children with cGVHD. In the first phase of the study, our aim is to evaluate the comprehension, clarity and ease of response of the PCSS through cognitive interviewing and to iteratively refine the measure to optimize content validity. In the second phase of the study, we will quantitatively examine the measurement properties of the PCSS in children and their caregiver-proxies. Eligible participants are children/adolescents ages 5-17 with cGVHD who are receiving systemic immunosuppressive treatment or have recently tapered to discontinuation. In the first phase, we are enrolling 60 child and caregiver-proxy dyads in three child age strata (5-7, 8-12, and 13-17 years old). Semi-scripted cognitive debriefing interviews are conducted to assess comprehension, clarity, and ease of response of each PCSS item with the child alone, and then jointly with the caregiver-proxy to explore discordant ratings. In phase two, an age-stratified cohort of 120 child-caregiver dyads will be enrolled to evaluate test-retest reliability, construct validity, and responsiveness. Anchors for known-groups validity include the PedsQL module and clinical variables, including cGVHD clinician-rated severity scores. In participants ages 13-17, we will also compare responses on the PCSS with those from the Lee cGVHD Symptom Scale, to gauge the youngest age at which adolescent respondents can comprehend this adult measure. This study will yield a well-validated, counterpart measure to the Lee cGVHD Symptom Scale for use in children with cGVHD and their caregiver-proxies. This new patient-reported outcome measure can be integrated into clinical trials and care delivery for pediatric transplant survivors to improve the precision and accuracy with which their cGVHD symptom experience is captured. www.ClinicalTrials.gov, NCT04044365.

Determinants and Clinical Significance of Musculoskeletal Symptoms in Patients With Chronic Graft-Versus-Host Disease.

Musculoskeletal symptoms in chronic graft-versus-host disease (cGVHD) are rare manifestations contributing to disease burden. This study assesses the frequency of muscle cramps, joint and muscle aches, and muscle weakness in a cohort of patients severely affected by cGVHD. Three hundred thirty-four patients participated in the NCI natural history study of cGVHD (NCT00092235) from October 2004 to March 2017. Five-point Lee cGVHD Symptom Scale was dichotomized (less symptom bother—0, 1, 2; severe symptom bother—3, 4) and tested for associations with: Short Form 36 (SF36), 2-minute walk test, grip strength, joint range of motion, and human activity profile, clinical and laboratory data. Seventy-five point four percent of patients reported joint and muscle aches (36.8% severe, Lee Symptom Scale score 3–4), 74.3% muscle cramps (33.5% severe), and 82.34% muscle weakness (45.51% severe), which were associated with reduced functional capacity (SF36 Physical Component Scale, P < 0.0001). Muscle cramps were associated with limited joint movement (P < 0.0001) and skin manifestations (skin thickening, P = 0.0008; itchy skin, P = 0.0003). Muscle cramps did not show association with potential causative agents, such as concomitant calcineurin inhibitors therapy, statins, or use of antidiabetic drugs. Joint and muscle aches showed associations with multiple variables (including strong associations with mood symptoms and fatigue, P < 0.0001). Muscle weakness was not associated with steroid dose, but was significantly associated with depression (P < 0.0001) and anxiety (P = 0.0009). This study documents a high frequency of musculoskeletal symptoms in a cohort of adult patients with cGVHD. The multivariable logistic regression models showed that a joint set of factors were moderately well associated with musculoskeletal symptoms in this study.

Initial Results of KD025-208: A Phase 2a Open Label Trial of KD025 for Steroid-Dependent Chronic Graft Versus Host Disease

Introduction: cGVHD occurs in approximately 50% of patients undergoing allogeneic hematopoietic stem cell transplantation and it remains a leading cause of post-transplant morbidity and mortality. cGVHD typically exhibits features of both autoimmune and fibrotic diseases and can affect single or multiple organ systems. Corticosteroids are the primary treatment modality and while not uniformly effective, often cause additional adverse effects in patients with prolonged use. Despite major advances in the understanding of cGVHD biology, no targeted therapy has been approved for cGVHD. KD025 is an orally available Rho-associated coiled-coil kinase 2 (ROCK2) selective inhibitor currently in Phase 2 clinical development for autoimmune and fibrotic indications. KD025 has been shown to downregulate pro-inflammatory T helper 17 cells and T follicular helper cells while upregulating anti-inflammatory regulatory T cells, which may potentially correct the immunological imbalance seen in cGVHD.Methods: Seventeen adult patients were enrolled in KD025-208, a Phase 2a, open-label study. Enrollment is planned for three cohorts (200 mg QD, 200 mg BID, and 400 mg QD) of 16 steroid-dependent cGVHD patients per cohort. The primary activity endpoint is the percentage of patients who meet the NIH Consensus Conference-defined overall response criteria (Partial Response (PR) + Complete Response (CR)) at 24 weeks. Secondary efficacy endpoints include changes in corticosteroid and calcineurin inhibitor dose and changes in cGVHD severity using the Physician-Reported Global cGVHD Activity Assessment. Exploratory endpoints include changes in symptom burden/bother using the Lee cGVHD Symptom Scale.Results: Seventeen patients with a median age of 50 years, median time from transplant to cGVHD diagnosis of 9.1 months, median time from initial cGVHD diagnosis to KD025 treatment initiation of 25.9 months, and median number of prior treatment regimens of three were enrolled in the 200 mg QD cohort. KD025 demonstrated an overall response rate (PR or CR at any evaluation time point) of 71% (12/17). Three patients discontinued KD025 treatment prior to 24 weeks (one cancer relapse, one cGVHD progression, and one adverse event of headache). Each of the three discontinued patients had demonstrated responses (PR) prior to study discontinuation. Fourteen of 17 (82%) patients remained on treatment at 24 weeks. At week 24, KD025 demonstrated clinical responses (CR or PR) in 57% (8/14) of the remaining evaluable patients. In addition to the eight responders, four patients had stable disease (SD) at 24 weeks; therefore, CR, PR or SD occurred in 86% (12/14) of patients. Importantly, of patients remaining on treatment at 24 weeks, 57% (8/14) had a reduction in steroid dose and 67% (4/6) had a reduction in tacrolimus dose. Moreover, 57% (8/14) of patients had a reduction in symptoms as measured by the Lee cGVHD Symptom Scale score. Patients with PR or SD were permitted to remain on KD025 for an additional 24 weeks. Eleven of 14 patients elected to remain on KD025 treatment after 24 weeks. Two patients were discontinued due to lack of response at 24 weeks and one patient with stable cGVHD was discontinued due to an unrelated adverse event of nephrotic syndrome.In addition, KD025 demonstrated an overall clinical benefit rate (PR or CR at any evaluation time point or SD at 24 weeks) of 88% (15/17) in all cGVHD patients.No treatment-related serious adverse events (SAEs) have been reported and no definitive treatment-related elevations in liver function tests (LFTs) (ALT, AST, ALP, and Bili) have been observed. Elevations in LFTs were commonly observed prior to KD025 dosing and may be attributable to cGVHD liver involvement. KD025 has been well tolerated and the overall adverse event profile appears consistent with cGVHD. Other low-grade treatment emergent adverse events seen in three or more patients were anemia (24%), diarrhea (24%), and nausea (24%).Conclusions: Treatment of cGVHD with KD025 demonstrated encouraging clinical responses and a favorable safety profile in patients with steroid-dependent cGVHD when administered at 200 mg QD. Eight of 14 patients (57%) demonstrated a 2014 NIH Consensus Conference-defined PR. No drug-related SAEs were reported. Enrollment in the dose-escalating cohorts is ongoing. DisclosuresLee:Kadmon: Other: One-time advisory board member; Bristol-Myers-Squibb: Other: One-time advisory board member; Amgen: Other: One-time advisory board member; Mallinckrodt: Honoraria. Salhotra:Kadmon: Consultancy. Jagasia:Mallinckrodt: Consultancy; Janssen: Consultancy, Research Funding; Therakos: Consultancy, Research Funding. Schueller:Kadmon: Employment, Equity Ownership.

An Open-Label, Single-Arm, Multicenter Study of Ibrutinib in Japanese Patients With Steroid-dependent/Refractory Chronic Graft-Versus-Host Disease

Chronic graft-versus-host disease (cGVHD) is a serious complication after allogeneic stem cell transplantation. There are no well-established treatment options for cGVHD after primary steroid-based treatment. Ibrutinib showed clinical benefit with an acceptable safety profile in steroid-dependent/refractory cGVHD patients in a Phase 1b/2 study (PCYC-1129-CA, NCT02195869), with which it was approved in the United States for adult cGVHD patients after failure of ≥1 systemic treatments. This open-label, single-arm, multicenter study was conducted to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of ibrutinib in Japanese patients ≥12 years of age with steroid-dependent/refractory cGVHD (NCT03474679). Patients were assessed on the basis of the National Institutes of Health (NIH) Consensus Development Project Criteria for Clinical Trials in cGVHD (2014). All patients received ibrutinib at a dose of 420 mg orally once daily, with a dose reduction to 280 mg/d on the concomitant use of voriconazole. Nineteen patients, including 1 adolescent, were enrolled and treated with ibrutinib in the study. At the time of clinical data cutoff (when the last patient completed the efficacy assessment at week 37), 10 of 19 patients (52.6%) remained on treatment whereas 9 of 19 patients (47.4%) had discontinued ibrutinib. The median duration of ibrutinib treatment was 9.63 (range 0.6 to 16.7+) months. The best overall response rate was 73.7%, and the rate of sustained response for ≥20 weeks was 71.4% for the responders (52.6% of all patients). Responses were seen across all the involved organs for cGVHD. Median daily corticosteroid dose requirement decreased by 0.06 mg/kg/d from baseline to week 36, whereas an improvement in the Lee cGVHD Symptom Scale score was observed in 42.1% of patients. The most common treatment-emergent adverse events (TEAEs) were pneumonia and stomatitis (36.8% each), upper respiratory tract infection (31.6%), cellulitis and platelet count decreased (26.3% each), and nausea (21.1%). Furthermore, 11 of 19 patients (57.9%) were reported with ≥1 treatment-emergent serious adverse events; the most common being pneumonia (26.3%) and cellulitis (15.8%). In total, 4 of 19 patients (21.1%) died during the study, of which 3 of 19 patients (15.8%) had TEAEs leading to death whereas 1 patient died of peritonitis, which occurred >30 days after the last dose of ibrutinib. Treatment-emergent adverse events leading to ibrutinib discontinuation were reported in 3 of 19 patients (15.8%). Ibrutinib was rapidly absorbed with a median time to reach maximum plasma concentration (tmax) of ~4.0 hours. Steady-state exposures were ~3.0- and ~1.4-fold higher for the patients receiving fluconazole (n = 8) and voriconazole (n = 4) with ibrutinib, respectively, as compared with patients not receiving CYP3A inhibitors (n = 7). Mean Bruton's tyrosine kinase occupancy was 88.1% at 4 hours after dose on day 1, and occupancy levels were maintained throughout the assessment period, regardless of the ibrutinib daily dose. Ibrutinib showed a clinically meaningful response and an acceptable safety profile in Japanese patients with steroid-dependent/refractory cGVHD; the safety profile was consistent with the known safety profile of ibrutinib in adults and with that seen in cGVHD patients receiving concomitant steroid treatment. Overall, the results were generally consistent with findings observed in the PCYC-1129-CA study.

Clinical Characterization and Cytokine Profile of Fatigue in Patients with Chronic Gvhd

Introduction Chronic graft-versus-host disease (cGVHD) is an autoimmune-like condition caused by allogeneic hematopoietic stem cell transplantation. It is the major cause of non-relapse mortality and morbidity after transplant. The majority of patients with cGVHD experience longstanding fatigue that is associated with decreased quality of life and impaired physical functioning. The pathophysiology and clinical characteristics of fatigue in cGVHD remain poorly understood and no effective treatments exist. Methods This cross-sectional study aimed to describe characteristics of fatigue experienced by patients with cGVHD using SF-36 self-report vitality scale as the primary outcome. 109 patients with fatigue and 72 patients without fatigue were prospectively enrolled and compared using a set of clinical, demographic and behavioral data along with 7 potential cytokine biomarkers of active cGVHD (IFN- γ, IL-6, CXCL-10, MCP-1, CXCL-9, BAFF, ST2). IFN- γ, IL-6, IP-10, and MCP-1 were assayed using V-PLEX by from Meso-ScaleDiscovery (MSD). The BAFF, CXCL9, and ST2 high sensitive assays were developed and customized for clinical testing using MSD electrochemiluminescence immunoassay technology with antibody pairs obtained from R&amp;D Systems. A patient was considered fatigued if SF-36 vitality score was &gt;10 points below the mean of the general population (&lt;40). Results The median Lee cGVHD symptom scale energy score was 6 (1-12) in fatigued individuals as compared to 3 (0-9) in non-fatigued individuals (P=0.0001) suggesting internal validity of the primary endpoint definition. SF-36 MCS and PCS scores were also significantly lower in the fatigued group by 10 points (P=0.0001 for both). Several measures including walk velocity, human activity profile, SF-36 physical and mental health self-report scales were potential predictors of fatigue in univariate analysis (Table 1). Patients with increasing levels of joint involvement were more likely to be fatigued (72% vs 60% with any involvement, p= 0.0067 for increasing involvement score). In addition, fatigued individuals had higher Lee cGVHD symptom burden in skin, breathing, muscles and joints and mental domains. None of the tested cytokines showed significant association with fatigue, even after stratification for time elapsed after cGVHD diagnosis to study enrollment. However, BAFF was shown to decrease in a consistent manner when more time elapsed from cGVHD diagnosis to study enrolment (p=0.015). BAFF levels were significantly associated with NIH joint score, NIH skin score, intensity of immunosuppression and Karnofsky performance status, thus confirming the usefulness of BAFF as a marker of cGVHD activity or severity, but not fatigue. Similarly, none of standard clinical laboratory serum markers of inflammation (e.g. ESR, CRP, C3, C4, albumin) showed significant association with fatigue. Multivariable analysis revealed that NIH joint score (P=0.03), Lee symptom scale sleep (P=0.0004) and depression (P=0.03) questions and PG-SGA nutrition score (P=0.0007) were predictors of fatigue after adjusting for confounders. Antidepressant use or sleep medication use did not differ significantly between the 2 groups (p=0.63 and 0.51, respectively), although patients reporting depression and sleep problems were more likely to be in the fatigued group, thus delineating a potential area for intervention and increasing quality of life. After adjusting for NIH lung score and performance status, known poor predictors of survival in this patient population, fatigue was associated with a slight trend toward lower probability of survival, median 130.6 months vs. median not reached (p=0.074) for fatigued and non-fatigued respectively (HR: 1.45, CI 0.88 to 2.40). Conclusions These results demonstrate that the pathophysiology of fatigue in cGVHD may involve mechanisms other than those reflected by cytokine markers of inflammation known to be associated with disease activity or severity. Musculoskeletal and lung involvement as well as decreased functional performance and capacity are significant features of fatigued patients with cGVHD. Sleep, nutrition and depression may be important therapeutic targets in these patients affected by clinically significant fatigue. Further studies involving longitudinal follow-up and deeper studies of biology are imperative to better understand or treat fatigue in cGVHD patients. Disclosures No relevant conflicts of interest to declare.

PCN479 PATIENT-REPORTED SYMPTOM BURDEN OF CHRONIC GRAFT VERSUS HOST DISEASE: A SYSTEMATIC LITERATURE REVIEW

Chronic graft versus host disease (cGVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). This study provides a systematic review of evidence on the patient-reported symptom burden of cGVHD. Systematic literature review was performed using PubMed, Scopus and Cochrane Controlled Register of Trials databases. Literature search was limited to English-language articles published after 2005. Only studies which used the National Institutes of Health (NIH) Consensus Criteria for diagnosing cGVHD and collected patient-reported symptom burden data were included. From the 1211 found references, 122 collected patient-reported data. There were 38 studies which specifically collected symptom burden data from patients, from which 35 used the 2005 and 3 used the 2014 NIH Consensus Criteria to define cGVHD. Different study designs were applied, the most frequently used were prospective (n=18) and cross-sectional cohort study (n=10). The number of involved cGVHD patients ranged from 19 to 584. Majority (n=28) of the studies were conducted in the USA. The Lee cGVHD Symptom Scale was the most frequently used instrument, applied in 28 studies. The NIH symptom scores reported by patients were also used frequently to assess organ-specific symptoms. The other instruments were mainly organ-specific measures (e.g. Ocular Surface Disease Index) or general measures to assess pain (e.g. Visual Analog Scale). Twenty-one studies were organ-specific; oral and ocular cGVHD were the most frequently investigated with 8 and 7 studies, respectively. Severity of the disease seems to be associated with higher symptom burden. The patient-reported symptom burden among patients diagnosed with cGVHD by NIH Consensus Criteria was widely assessed in the literature. The Lee Symptom Scale is the most frequently used instrument in trials. Organ involvement and disease severity are both important factors of the cGVHD’s symptom burden. New treatment options should aim to mitigate symptom burden of cGVHD patients.

PS1533 KD025–208: A PHASE 2A TRIAL OF KD025 FOR PATIENTS WITH CHRONIC GRAFT‐VERSUS‐HOST DISEASE (CGVHD) – UPDATED SAFETY AND EFFICACY

Background:KD025 is an inhibitor of ROCK2 in a pivotal clinical trial for chronic graft‐versus‐host disease (cGVHD). Inhibition of ROCK2 downregulates TH17 and Tfh cells while upregulating regulatory T (Treg) cells, helping to resolve the immune dysregulation seen in cGVHD. In addition, KD025 decreases myofibroblast formation and proliferation, inhibiting the fibrotic components of cGVHD.Aims:KD025–208 is an open‐label, Phase 2 study of KD025 in patients with steroid‐dependent or refractory cGVHD.Methods:Three cohorts (200 mg QD [n = 17], 200 mg BID [n = 16] and 400 mg QD [n = 21]) were enrolled sequentially. The primary endpoint is the overall response rate, defined per the 2014 NIH Consensus criteria.Results:Patients enrolled in all three cohorts received a median of 2 prior lines of cGVHD therapy. The median corticosteroid dose at baseline was 0.19 mg/kg/day. The most frequently involved organs were eyes (78%), skin (74%), mouth (65%), joints/fascia (61%) and lungs (31%). Forty‐eight percent (48%) of patients had involvement of ≥ 4 organs. As of 13 September, 2018, twenty patients (6 in Cohort 1, 3 in Cohort 2 and 11 in Cohort 3) remain on treatment with KD025, with a median treatment duration of 89, 68 and 34 weeks, respectively. The Overall Response Rate (ORR) was 65% in Cohort 1, 63% in Cohort 2 and 52% in Cohort 3. Responses were rapid, with 75% of responders achieving a response by the first assessment (at 8 weeks). Nine of 11 responders (82%) in Cohort 1 have sustained a response for ≥ 20 weeks. In patients with ≥ 2 prior lines of therapy and in patients with ≥ 4 organs involved, the ORR pooled across the cohorts was 58% and 62%, respectively. Responses were observed across all affected organ systems, including CRs in upper GI, lower GI, esophagus, mouth, skin, joints, eyes and liver. Two partial responses were observed in lung. The median corticosteroid dose reduced by 44% in Cohort 1, 23% in Cohort 2 and 10% in Cohort 3 while on study. Seven patients completely discontinued corticosteroid treatment while receiving KD025. Seventy‐two percent (72%) of responders across all three cohorts achieved a clinically meaningful improvement (≥ 7‐point reduction) in the Lee cGVHD Symptom Scale Score. KD025 was well tolerated. Commonly reported AEs were URTI, AST/ALT elevations, fatigue, nausea and diarrhea. SAEs occurred in 20 patients; none were related to KD025. No increased risk of infection was observed and no CMV infections were reported. Eighteen of 54 patients discontinued treatment due to progression of cGVHD, 6 due to voluntary withdrawal, 3 due to recurrence of underlying malignancy, 2 due to an AE, 2 due to death, 2 due to investigator decision and 1 due to noncompliance. Preliminary pharmacodynamic results demonstrate a decrease in TH17 cells and an increase in Treg cells in responders to KD025 treatment, consistent with the proposed mechanism of action. Failure‐free survival (FFS) data will be presented for the first time at the EHA meeting.Summary/Conclusion:Treatment with KD025 has resulted in clinically meaningful and durable responses across all affected organ systems. Corticosteroid doses were reduced in both responders and non‐responders. KD025 treatment was well tolerated with an AE profile consistent with that expected in cGVHD patients receiving corticosteroids. No apparent increased risk of infection was observed. Pharmacodynamic results support the proposed KD025 mechanism of action. FFS data will be presented at the meeting.

PB2320 PHASE II STUDY OF IMATINIB MESYLATE PLUS MYCOPHENOLATE MOFETIL FOR PEDIATRIC STEROID‐REFRACTORY SCLEROTIC/FIBROTIC TYPE CHRONIC GRAFT‐VERSUS‐HOST DISEASE

Background:Chronic graft‐versus‐host disease (cGVHD) is the most common late complication following allogeneic stem cell transplantation. Sclerotic/fibrotic cGVHD is one of the severe type, and often refractory to standard and secondary therapy.Aims:In this study, we evaluated the efficacy and safety of imatinib mesylate and mycophenolate mofetil (MMF).Methods:In non‐randomized, open‐label, single‐arm, multi‐center, prospective phase II study, we enrolled patients with steroid‐refractory sclerotic/fibrotic type cGVHD. Participants were treated with MMF at a dose of 15‐20 mg/kg (maximum 1 g) bid and imatinib mesylate at the initial dose of 260 mg/m2/day (maximum 400 mg) in combination with previous cGVHD treatment. The primary endpoints was overall (complete and partial) response rate at 1 year. Secondary endpoints included safety, quality of life, discontinuation of steroid and overall survival (OS) rate.Results:A total of 13 patients were enrolled between October 2013 and July 2017. The median age was 10.4 years (range 5.0‐20.1 years). Five of the 13 patients had previously experienced acute GVHD. The diagnoses were acute lymphoblastic leukemia in 5, acute myeloid leukemia in 3, chronic granulomatous disease in 3, neuroblastoma in 1 and hemophagocytic lymphohistiocytosis in 1 patient. Nine of the 13 patients achieved partial response (PR), 2 showed stable diseases (SD), and 1 died of pulmonary infection and progression of chronic lung GVHD. The remaining 1 patient died of primary disease progression. The overall response rate was 69.2 %. Nine of the 13 patients were able to reduce or discontinue steroids. Among 13 patients, 6 patients showed improvements in Lee cGVHD symptom scale score to assess quality of life. Common adverse events included grade 1‐2 liver enzyme, creatinine elevations and fever. The 2‐ and 5‐year OS rate was 76.9% and 67.3%, respectively.Summary/Conclusion:Although limited by a small sample size, Gleevec plus MMF for cGVHD showed promising results with acceptable toxicity.

A randomized, double-blind phase III study of ibrutinib versus placebo in combination with corticosteroids in patients with new onset chronic graft versus host disease.

TPS7072 Background: Chronic graft versus host disease (cGVHD) is a common complication of allogeneic stem cell transplantation, with pathophysiology involving alloreactive and dysregulated T and B cells and innate immune populations. Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is indicated by the US FDA for the treatment of patients (pts) with CLL/SLL. Ibrutinib recently received breakthrough therapy and orphan drug designation for the treatment of pts with cGVHD who did not respond to one or more lines of systemic therapy. Ibrutinib reduces severity of cGVHD in murine models and recently was shown to achieve an NIH-defined overall response rate of 67% in pts with steroid relapsed/refractory cGVHD (Miklos Blood 2016). Methods: The primary objective of this Phase 3, multicenter, international, randomized, controlled, double-blind study is to evaluate the 24-week response rate of ibrutinib versus placebo in combination with prednisone. Pts with newly diagnosed moderate or severe cGVHD, as per NIH Consensus Development Project Criteria (2014), will be randomized in a 1:1 ratio to receive either oral ibrutinib (arm A) or placebo (arm B) in combination with oral prednisone. Ibrutinib or placebo will be given until unacceptable toxicity, relapse of underlying disease, death, or the need for a new systemic treatment for progressive cGVHD. Eligible study pts (age ≥12 yrs) must require systemic treatment with corticosteroids and have no prior systemic treatment for cGVHD. The primary endpoint is response rate (complete or partial response) at 24 weeks, as per NIH Consensus Development Project Criteria, and must occur in the absence of both new therapy for cGVHD and relapse/return of the underlying disease that was the indication for transplant. Secondary endpoints will assess for additional clinical benefit including corticosteroid dose reduction, improvement of Lee cGVHD Symptom Scale scores, withdrawal of all immunosuppressants, and overall survival. This study is currently enrolling pts. Funding source: Pharmacyclics LLC, an AbbVie Company. Clinical trial information: NCT02959944.

Multicenter Open-Label Phase 2 Study of Ibrutinib in Chronic Graft Versus Host Disease (cGVHD) after Failure of Corticosteroids

Background: Chronic GVHD (cGVHD) is a serious complication of allogeneic stem cell transplantation. Effective therapy for patients (pts) with cGVHD who fail corticosteroids remains an unmet medical need. Both B and T cells play a role in the pathophysiology of cGVHD. In preclinical models, ibrutinib (ibr) reduced the severity of cGVHD through its inhibition of Bruton9s tyrosine kinase (BTK) and interleukin-2-inducible T-cell kinase (ITK) (Dubovsky, J Clin Invest 2014). Ibr has recently been granted a breakthrough therapy designation (BTD) for cGVHD after failure of 1 or more lines of systemic therapy. The request for a BTD was supported by early data from a phase 2 study that evaluated the efficacy and safety of ibr in pts with cGVHD who are in need of additional therapy. The final results of this same study are presented here. Methods: Pts who had received ≤3 prior regimens for cGVHD and had either >25% body surface area erythematous rash or a National Institutes of Health (NIH) mouth score >4 were treated with daily ibr (420 mg) until cGVHD progression or unacceptable toxicity. The primary end point was cGVHD response based on the 2005 NIH consensus response criteria. Secondary end points included rate of sustained response, change in Lee cGVHD symptom scale, changes in corticosteroid requirement over time, and safety end points. The effects of ibr on lymphoid and myeloid cell signaling pathways, and phenotype along with plasma cytokines and chemokines were evaluated. Results: A recommended phase-2 dose of 420 mg was identified in phase 1b (n=6) with no dose-limiting toxicities reported. Of 42 pts treated with ibr, median age was 56 y (range, 19-74). Median duration of cGVHD before study entry was 13.7 mo (range, 1.1-63.2). Median number of prior regimens was 2 (range, 1-3). At a median follow-up of 13.9 mo, overall response rate (ORR) was 67% (28/42 pts; 9 [21%] CR, 19 [45%] PR), with 20/28 (71%) and 12/25 (48%) responders showing a sustained response of ≥20 and ≥32 weeks, respectively (Figure 1). Overall, 21 responders (75%) had corticosteroid doses 3 pts were pneumonia (n=6), fatigue (n=5), and diarrhea (n=4). Serious AEs (SAEs) occurred in 22 pts (52%); grade ≥3 SAEs reported in 17 pts (40%) included pneumonia (n=5), septic shock (n=2), and pyrexia (n=2). Two fatal events (multilobular pneumonia and bronchopulmonary aspergillosis) were reported. Five pts discontinued therapy for progressive cGVHD and 14 for AEs including fatigue (n=3) and pneumonia (n=2). Twelve pts (29%) continued ibr; their treatment duration ranges from 5.6-24.9 mo. Conclusions: With an ORR of 67% and a sustained response rate of ≥20 weeks of 71%, treatment with ibr resulted in clinically meaningful and durable responses in pts who failed at least 1 prior treatment for cGVHD. Most responders were able to reduce steroid dose to an acceptable minimal level. Biomarker changes support an effect of ibr on immune cell subsets in pts with cGVHD. Reported AEs are consistent with those for ibr in B-cell malignancies and pts with cGVHD. Observed response rates in this pretreated, high-risk population support further study of ibr for frontline treatment of cGVHD. Disclosures Miklos: Pharmacyclics, LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, and Expenses, Research Funding; Kite Pharma: Research Funding; Roche: Research Funding; Novartis: Research Funding; Sanofi Oncology: Other: Travel, Accommodations, and Expenses. Cutler: Insys: Consultancy; Seattle Genetics: Consultancy; Regimmunie: Consultancy; Incyte: Consultancy. Arora: Takeda Oncology: Consultancy; Pharmacyclics, LLC, an AbbVie Company: Research Funding. Waller: Cerus: Equity Ownership; Chimerix: Equity Ownership; Cambium Medical Technologies: Equity Ownership, Other: Other relationship indicated, Patents & Royalties; Novartis: Consultancy, Honoraria, Research Funding; Helocyte: Consultancy. Jagasia: Theracos: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Flowers: Pharmacyclics, LLC, an AbbVie Company: Research Funding. Logan: Amgen: Consultancy; Jazz: Consultancy; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; Astellas: Research Funding; Novartis: Research Funding. Nakamura: Seattle Genetics: Consultancy; Amgen: Consultancy. Blazar: Tobira Therapeutics: Consultancy; Vulcan CApital: Consultancy; Idera Pharma: Consultancy; Sidley Austin LLP: Consultancy; Merck Serono: Consultancy; Fate Therapeutics: Consultancy; Merck, Sharpe & Dohme Corp: Consultancy; Bristol-Myers Squibb: Consultancy; Kadmon Pharmaceuticals Inc: Consultancy, Research Funding; Kymab: Consultancy; Five Prime Therapeutics: Consultancy; Vitae Pharmaceuticals, Inc.: Consultancy; Flx Bio: Consultancy; No Company: Patents & Royalties: no company. Li: Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Lal: AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment; Infinity: Equity Ownership; Clovis: Equity Ownership; Reviva Pharmaceuticals: Equity Ownership; The Permanente Medical Group: Employment, Equity Ownership; Gilead Sciences: Employment, Equity Ownership. Dubovsky: Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. James: Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Styles: Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Jaglowski: Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding.

Translation, Cross-Cultural Adaptation, and Validation of the Lee Chronic Graft-versus-Host Disease Symptom Scale in a Brazilian Population

The Lee Chronic Graft-versus-Host Disease (GVHD) Symptom Scale is a patient-reported instrument developed and validated in English to measure the symptoms and functional impact of cGVHD. This tool has not yet been validated in a Latin American population, however. The Brazil-Seattle Chronic GVHD Consortium conducted a multicenter study at 5 Brazilian institutions to validate the Lee cGVHD Symptom Scale in adults with cGVHD. Study objectives included the translation and validation of the instrument in Brazilian Portuguese and evaluation of the correlation with other quality of life (QoL) tools, including the Medical Outcomes Study Short Form 36 (SF-36) and Functional Assessment of Chronic Illness Therapy with Bone Marrow Transplant subscale (FACT-BMT). Translation and validation were done according to the American Association of Orthopedic Surgeons Outcome Committee guidelines. Spearman's correlation coefficient was used to measure construct validity. Reliability was assessed using Cronbach's α and intraclass correlation coefficients. Between April 2011 and August 2012, 47 patients with cGVHD based on the 2005 National Institutes of Health criteria (29 males [62%], 18 females [38%]; median age, 48 years; range, 23 to 69 years) were enrolled in this study. The reliability of the Lee cGVHD Symptom Scale was adequate (Cronbach's α = 0.62 to 0.83). The correlations between similar domains of the Lee cGVHD Symptom Scale, SF-36, and FACT-BMT were moderate to high. Our data indicate that the Brazilian Portuguese version of the Lee cGVHD Symptom Scale is valid and reliable and can be used in clinical trials of cGVHD in Brazil.

Prevalence and determinants of fatigue in patients with moderate to severe chronic GvHD.

Although fatigue is common after allogeneic hematopoietic cell transplantation, little is known about fatigue in patients with chronic GvHD (cGvHD). The aim of this study was to explore factors associated with fatigue in cGvHD. Data were drawn from a sequentially recruited, cross-sectional study of adults with moderate or severe cGvHD (n=263). Respondents were classified as fatigued or not fatigued based on their response to a single item regarding loss of energy from the Lee cGvHD Symptom Scale. In univariate analysis, factors significantly associated with fatigue included performance status, number of prior cGvHD therapies, cGvHD symptom bother, self-assessed physical and mental health, nutritional status, walk velocity and self-reported physical activity. There were no significant associations between fatigue and disease-related cGvHD variables. Multivariable logistic regression demonstrated that being less active and having pulmonary and/or muscle/joint symptoms were independently associated with fatigue. In conclusion, clinically significant fatigue was prevalent in more than one-third of subjects with cGvHD, and was disabling. Absence of association with measures of cGvHD severity underscores the need to elucidate the pathogenesis of fatigue and its relationship with inflammatory activity. Pulmonary and muscle/joint symptoms and physical inactivity represent potential targets for intervention in clinical studies.

Content Validity of the Lee Chronic Graft-versus-Host Disease Symptom Scale as Assessed by Cognitive Interviews

The Lee Chronic Graft-versus-Host Disease (cGVHD) Symptom Scale has been recommended for use by the 2005 and 2014 National Institutes of Health (NIH) Consensus Conferences to capture cGVHD symptoms. Although the cGVHD Symptom Scale was previously validated, this study aims to reexamine the instrument's content validity by exploring the clarity, comprehensibility, relevance, and ease of use in a contemporary cGVHD sample, toward Food and Drug Administration (FDA) qualification of this patient-reported outcomes (PRO) instrument as a drug development tool. Attaining FDA qualification means that an instrument has been judged to be a reliable and valid measure of clinical benefit. Twenty adult patients with a median age of 58 year (range, 31 to 79 years) participated. The median duration of cGVHD was 33 months (range, 0 to 134.4 months), and current NIH severity score was mild in 1 patient, moderate in 10 patients, and severe in 9 patients, with a median of 5.5 treatments (range, 0 to 14) ever used for cGVHD. The median summary score was 23 (range, 8 to 51), and the median time to complete the scale was 2 minutes, 7 seconds (range, 1 minute, 8 seconds to 4 minutes). Symptoms of cGVHD were well captured on the Lee cGVHD Symptom Scale, although 4 additional symptoms/signs were mentioned by 15% of the participants. Participants mostly reported that item wording was clear and provided accurate definitions of specific terminologies; however, 7 participants (35%) reported finding 1 or more items in the skin domain unclear, reporting, for example, that rashes and itchy skin seemed synonymous. Two of 19 participants (10.5%) described how their answers would have changed had they been asked about their symptoms within the past month instead of within the past week, owing to recently resolved symptoms. All participants were able to accurately explain the concept of “bother” in their own words and distinguish it from symptom severity or other related symptom attributes. In summary, participants found the Lee GVHD Symptom Scale to be a comprehensive and understandable way to report their cGVHD symptom experience. Future work will focus on options for the recall period, the phrasing of skin items, and whether some very rare symptoms (eg, feeding tube, use of oxygen) should continue to be a part of the scale.

A survey of fertility and sexual health following allogeneic haematopoietic stem cell transplantation in New South Wales, Australia.

Four hundred and twenty-one adult allogeneic haematopoietic stem cell transplant (HSCT) survivors participated in a cross-sectional study to assess sexual dysfunction and infertility post-transplant. Survey instruments included the Sydney Post-Blood and Marrow Transplant (BMT) Survey, Functional Assessment of Cancer Treatment (FACT) - BMT, the Depression, Anxiety, Stress Scales (DASS 21), the Chronic Graft-versus-Host Disease (cGVHD) Activity Assessment- Patient Self Report (Form B), the Lee cGVHD Symptom Scale and The Post-Traumatic Growth Inventory. Most HSCT survivors reported sexual difficulties (51% of males; 66% of females). Men reported erectile dysfunction (79%) and decreased libido (61·6%) and women reported loss of libido (83%), painful intercourse (73%) and less enjoyment of sex (68%). Women also commonly reported vaginal dryness (73%), vaginal narrowing (34%) and vaginal irritation (26%). Woman had much higher rates of genital cGvHD than men (22% vs. 5%). Age and cGVHD were significantly associated with sexual dysfunction. Few survivors had children following transplant (3·3%). However, for those of reproductive age at HSCT, 22% reported trying to conceive, with 10·3% reporting success. This study is the largest to date exploring sexual function in survivors of allo-HSCT. This data provides the basis for health service reform to better meet the needs of HSCT survivors, including evidence to support counselling and education both pre- and post-transplant.

Clinical and Immunologic Characteristics of Patients with Chronic Graft-Versus-Host Disease Persisting Seven or More Years after Diagnosis

BackgroundChronic graft-versus-host disease (cGVHD) is a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplant (SCT). Median duration of systemic immunosuppression (IS) for cGVHD is approximately 2 years; however, 15% of patients still require IS 7 years after SCT. Previous studies identified factors that were associated with longer duration of IS or cGVHD. Our aim was to identify clinical and immunologic factors associated with cGVHD that is persistent ≥7 years after cGVHD diagnosis.MethodsPatients were drawn from a prospective cross-sectional study of the natural history of cGVHD at the National Institutes of Health (NCT00092235). A cohort of patients who enrolled on the study ≥7 years from the time of cGVHD diagnosis, and thus had persistent cGVHD (pcGVHD), was compared to those who enrolled <1 year from cGVHD diagnosis. Univariate analysis was performed, and significant factors were used in multivariable logistic regression. With a large number of exploratory variables, all p-values<0.005 were considered statistically significant; 0.005≤p <0.05 represented strong trends.ResultsThere were 38 patients with pcGVHD and 83 control patients <1 year from cGVHD diagnosis. The two groups did not differ in age or performance status. Factors that were significantly associated with pcGVHD (Table 1) included: bone marrow (BM) stem cell source (result divergent from previous studies), myeloablative conditioning, greater lung involvement, lower ferritin, lower IS, positive ENA (autoantibody panel), higher CD19 cells, CD4 cells, and immunoglobulin levels. Factors with a trend towards significance included female donor, higher Lee cGVHD symptom scale scores, more sclerotic skin involvement and less erythematous skin involvement, and more active cGVHD as determined by therapeutic intent at the time of evaluation. Interestingly, there were no differences in factors associated with disease severity (NIH global severity, clinician and patient rated severity, number of organs involved and organ scores), other inflammatory markers (ESR, CRP), functional capacity, distance from home to the transplant center, nor other factors identified in previous studies (bilirubin, HLA disparity). In a multivariable analysis that included 11 variables, BM stem cells, +ENA, higher NIH lung score, higher platelets, and higher IgA levels were significant independent predictors of pcGVHD.ConclusionsAlthough cGVHD is often self-limited, late forms requiring long duration of IS exist, and the predictive factors or underlying pathogenesis are unknown. Our analysis of cGVHD patients who enrolled on a clinical trial ≥7 years after diagnosis showed more lung and sclerotic skin involvement, less inflammatory signs, and higher B cells, immunoglobulins, and autoantibodies. These new findings suggest that pcGVHD may reflect irreversible damage rather than an active immune process; however, standardly accepted measures of disease severity were not associated with pcGVHD, suggesting that further tools are needed to differentiate accumulated damage from active disease. Distance from transplant center, which may contribute to access to care, was not associated, although increasing IS was recommended more frequently for pcGVHD patients. Factors that were previously identified as associated with longer duration of IS were not different or conflicted with our findings, suggesting that further study is needed. To further elucidate potential immune dysfunction in patients with pcGVHD, our ongoing studies are measuring BAFF, cytokine, and chemokine levels. Our results contribute to further hypotheses in the pathogenesis and contributing factors in patients who have pcGVHD.Table 1Univariate analysis - factors significantly associated with pcGVHD≥7 years from diagnosis (N=38)<1 year from diagnosis (N=83)p-valueBM stem cells (% patients)5811<.0001Myeloablative conditioning (% patients)8645<.0001+ENA (% patients)181.001NIH lung score (% with 2-3)5022.002Intensity of IS (% with mod/high)4780.0005Prednisone mg/kg/day*00.2.001Lee cGVHD symptom scale - breathing score*52.001FEV1*6993.001Platelets*278193<.0001Albumin*43.5<.0001Ferritin*1501240<.0001CD4 cells*534327.002CD19 cells*26687.0004IgG*756516.0005IgA*14532<.0001*median DisclosuresNo relevant conflicts of interest to declare.

Assessing response of therapy for acute and chronic graft-versus-host disease

Graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Currently, there are no formal guidelines for assessing the response to GVHD therapy, limiting clinical care and the development of clinical trials. There are proposals for assessing response to acute GVHD therapy. For example, response to therapy at day 28 is predictive of treatment-related mortality. Response to therapy at the same time point may also be predictive of overall survival. The NIH Response Criteria Working Group of the Consensus Conference has proposed guidelines that will help make collection of chronic GVHD (cGVHD) response data more uniform so that response assessment can be formally studied. Core measures of cGVHD including organ-specific assessments and the Lee cGVHD symptom scale were first proposed. In addition, provisional criteria for definition of response were suggested. Finally, biomarkers may provide a powerful tool for predicting response to GVHD therapy. A six-biomarker panel measured prior to the start of therapy has been described that predicts response to treatment at day 28 of therapy for acute GVHD. Further work will determine if biomarkers can be identified that can predict response to cGVHD therapy.

Personality influences quality-of-life assessments in adult patients after allogeneic hematopoietic SCT: results from a joint evaluation of the prospective German Multicenter Validation Trial and the Fred Hutchinson Cancer Research Center

The influence of personality on health related quality of life (QoL) and physical functioning in the setting of allogeneic hematopoietic SCT (alloHSCT) is unknown. We conducted a joint evaluation within two independent cohorts of alloHSCT recipients to investigate the impact of personality on reported QoL and physical functioning. Two-hundred-eight patients (median age 44 years, range 18-72) of cohort 1 and 93 patients (median age 55 years, range 19-79) of cohort 2 after alloHSCT were evaluated. Personality was assessed using the 24-adjective measure (AM), which measures the Big-Five personality domains and the Life Orientation Test-Revised (LOT-R), measuring optimism and pessimism. QoL was measured using the Functional Assessment of Cancer Therapy with bone marrow transplantation subscale (FACT-BMT), Short Form 36 (SF-36), the human activity profile (HAP), as well as the NIH criteria-based cGVHD activity assessment form and the Lee cGVHD symptom scale. Neuroticism was significantly associated with worse function measured by the HAP and FACT-BMT. Optimism significantly improved QoL captured by the FACT-BMT. Pessimism significantly impaired physical function captured by the HAP and SF-36. Extraversion was significantly associated with reduced depression and lower severity of cGVHD symptoms reported by the patient and the physician. The results suggest that personality traits and pre-treatment QoL assessments should be measured in clinical trials to facilitate the interpretation of QoL data.

Validation of the Human Activity Profile Questionnaire in Patients after Allogeneic Hematopoietic Stem Cell Transplantation

Chronic graft-versus-host disease (cGVHD) associated morbidity and mortality remain major barriers for successful allogeneic hematopoietic stem cell transplantation (alloHSCT). Currently, no reliable measures are established to monitor cGVHD activity changes for use in clinical trials. The Human Activity Profile (HAP) patient self-report was proposed by the National Institutes of Health (NIH) cGVHD consensus project as an independent measure of patients' functional status that could also indirectly reflect improvement of cGVHD, but that has not been validated in an alloHSCT patient population. One hundred seventy-six patients (median age 44 years [range: 18-72 years] after alloHSCT were evaluated with a German translation of the HAP, the NIH criteria-based cGVHD activity assessment, the Lee cGVHD Symptom-Scale, FACT-BMT, SF36, Berlin Social Support Scale, 24-Item Adjective Measure (24-AM), Hospital Anxiety and Depression Scale, and the NCCN-Distress-Thermometer. Enrollment occurred a median of 286 (range: 85-4003) days after alloHSCT. Follow-up surveys were conducted at 1, 2, 3, 5, 8, and 12 months after the baseline survey. Although 117 patient had cGVHD at time of enrollment (mild n = 33, moderate n = 50, or severe n=34), 59 patients were included into the study in the absence of cGVHD between days 85 and 395 after transplantation. The maximum activity score (MAS) and adjusted activity score (AAS) of the HAP correlated inversely with grading of cGVHD severity (mild, moderate, or severe) (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 physical functioning scale of the SF36. Performance was improved by use of an HSCT-modified HAP scoring system that excluded activities prohibited within the first year after alloHSCT. No significant correlation of the HAP was found with personality, age, sex, symptom burden, or social functioning or social well-being. Moreover, the HAP displayed a higher sensitivity to change of cGVHD activity compared to the SF36 and the FACT-BMT. In addition, steroid myopathy correlated with both HAP scores, but not the SF36. The HAP is a simple and valid questionnaire for the evaluation of the physical activity in patients after alloHSCT, with the advantage of detecting changes in cGVHD status independently of other quality-of-life measures and with a superior sensitivity compared to the SF36.

Salivary Gland Involvement in Chronic Graft-Versus-Host Disease: Prevalence, Clinical Significance, and Recommendations for Evaluation

Although xerostomia is a commonly reported complaint in patients with chronic graft-versus-host disease (cGVHD), criteria for evaluating the prevalence and characteristics of salivary gland involvement have not been well defined in this patient population. Previous studies also have made no distinction between salivary and mucosal oral cGVHD. We systematically evaluated signs and symptoms of sicca in a large cohort of patients with cGVHD (n = 101) using instruments widely used to study Sjogren's syndrome. Xerostomia was reported in 60 (77%) patients reporting ocular and 52 (67%) patients reporting oral complaints [corrected]. The salivary flow rate was < or =0.2 mL/min in 27%, and < or =0.1 mL/min in 16%. Histopathological changes, consisting of mononuclear infiltration and/or fibrosis/atrophy, were present in all patients with salivary dysfunction. Importantly, there was no correlation of salivary and oral mucosal involvement in cGVHD. Patients with cGVHD-associated salivary gland involvement had diminished oral cavity-specific quality of life and lower body mass index. Salivary gland involvement is a common and clinically distinct manifestation of cGVHD. Formal evaluation of salivary function using standardized criteria is needed, and this could be incorporated as an outcome measure in clinical trials of cGVHD.

Validation of the NIH Criteria of the Severity Grading of Chronic Gvhd – Results of a Prospective German Multicenter Validation Trial.

Abstract 204The NIH staging and response criteria offer for the first time the chance for uniform documentation of chronic graft-versus-host disease (cGVHD). Here we present the validation of the cGVHD staging criteria as part of an interim analysis of a prospective German/Austrian multicenter study on the NIH staging criteria in cGVHD. One hundred-seventeen patients (median age 44 years, range 21–72) after allogeneic hematopoietic stem cell transplantation (HSCT) were evaluated according to the NIH criteria based on cGVHD activity assessment including the NIH-cGVHD grading form, the physicians cGVHD activity assessment form, the NIH-cGVHD symptom self assessment form, and the Lee cGVHD symptom-scale (L-cGVHD-SC). Enrolment occurred a median of 443 (range, 100–4003) days after HSCT. The validation of the NIH staging criteria was performed using the first 3 surveys each one month apart. For the purpose of validity a second evaluation was performed including only patients with stable cGVHD (n=64) as judged by the physician (results in parentheses). The statistical significance p was <0.01 for all reported results. Severity of cGVHD was mild in 33 patients, moderate in 50, and severe in 34, respectively. For the global NIH cGVHD grading (mild, moderate, severe) the test-retest stability between the three evaluations showed a high correlation ranging from 0.67–0.75 (0.7–0.78). Interestingly, the physician′s severity grading using the 10 point scale demonstrated a higher correlation ranging from 0.82–0.87 (0.88–0.92). The test-retest stability was highest for skin: 0.82–0.85 (0.91–0.93), mouth: 0.7–0.75 (0.76–0.8) and joints: 0.75–0.79 (0.68–0.86) followed by liver: 0.58–0.76 (0.63), eye: 0.64–0.68 (0.6–0.62) and genital: 0.65–0.87 (0.83–0.95), while it was relatively low for gastrointestinal (GI): 0.43–0.44 (0.38) and lung manifestations: 0.46–0.49 (0.6) respectively. With regard to the patients' self assessment the test-retest stability ranged for the 10 point scale between 0.76–0.79 (0.8), and for the mild/moderate/severe grading from 0.68–0.75 (0.83–0.85). Mouth dryness was reported with a correlation of 0.74–0.79 (0.83–0.84), mouth pain with 0.68–0.79 (0.74–0.84) and mouth sensitivity with 0.77–0.80 (0.81–0.88). Eye complaints were reported with high stability: 0.82 (0.81–0.86). Comparison of physicians' organ grading with patients' organ specific self assessment of the NIH self assessment form and the L-cGVHD-SC organ scores revealed a moderate correlation of the physicians' skin grading with the skin L-cGVHD-SC subscale (r=0.55), the mouth grading with the mouth L-cGVHD-SC subscale (r=0.32), mouth dryness (r=0.42), mouth sensitivity (r=0.44), and mouth pain (r=0.5) of the NIH self assessment form. The physicians' eye grading correlated with the eye and mouth L-cGVHD-SC subscale (r=0.62) and eye complaints in the patients' NIH self assessment form (r=0.65). The lung grading correlated moderately with the breath subscale of the L-cGVHD-SC (r=0.5). While the joint grading correlated moderately only with the muscle and joint subscale of the L-cGVHD-SC, the GI grading did not correlate with the eating and digestion part of the L-cGVHD-SC. The results demonstrate a high test-retest stability for most of the organs and the global grading indicating its robustness in clinical use. The low test-retest correlation in the lung and GI grading including failure to correlate with the eating and digestion subscale of the L-cGVHD-SC may relate to the solely functional staging and the multifactorial pathogenesis of symptoms. This is supported by the correlation of lung symptoms in the L-cGVHD-SC breath subscale with lung grading. Disclosures:No relevant conflicts of interest to declare.