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BACKGROUND: Hematopoietic cell transplant (HCT) can cause significant distress in patients and their informal caregivers. Despite advances in reduced intensity conditioning and supportive care, few recent studies have reported rates of clinically-significant post-traumatic stress disorder symptomatology (hereafter referred to as PTSD). Goals of the current study were to: 1) examine rates of PTSD and distress in patients and caregivers and 2) identify sociodemographic and clinical risk factors for PTSD. METHODS: As part of an annual survivorship survey, 2,157 HCT recipients and their caregivers were mailed self-report measures of PTSD and distress. Patients also completed self-report measures of sociodemographic information (e.g., age, sex, employment status). Clinical variables (e.g., time since transplant, transplant type) were captured in the transplant database. RESULTS: A total of 691 recipients (56% age 60 or above at the time of survey, 47% female, median 10.1 years post-HCT) and 333 caregivers provided PTSD data and were included in the current analyses. More caregivers reported PTSD (6.6%) than patients (3.3%) (p=0.02). Patients or caregivers who had PTSD reported significantly higher distress related to uncertainty, family strain, medical demands, finances, identity, and health burden (p values < 0.0001) compared to those without PTSD. Patient but not caregiver PTSD was associated with more recent transplant (p=0.01, p=0.16). CONCLUSIONS: Rates of PTSD are relatively low in long-term survivors of HCT and their caregivers. Nevertheless, results are consistent with other studies of cancer caregiving suggesting that caregivers often experience greater distress than patients. Timely referral to psychosocial services should be offered to both HCT recipients and caregivers reporting symptoms of PTSD.

In 2014, the National Institutes of Health sponsored the second Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease (GVHD). The purpose was to update recommendations about key elements of chronic GVHD research, including definitions for diagnosis, severity scoring, and response measures, based on empirical data published since the first 2005 Consensus Conference. The most significant modifications were to the response assessments, based on studies demonstrating difficulty with the first consensus definitions. The Response Measures Validation Study is a multicenter, prospective cohort study of patients who are starting initial or subsequent treatments for chronic GVHD. The aim of the study is to evaluate the performance of the 2014 response measures and determine whether any other combination of assessments is superior. Clinical data, clinician assessments, patient-reported outcomes, and research samples are collected at enrollment and 3, 6, and 18 months later, and whenever another chronic GVHD systemic treatment is added. The target enrollment of 368 evaluable patients from 12 transplantation centers has been reached. This report describes the rationale, design, and methods of the Chronic GVHD Response Measures Validation Study, and invites other investigators to collaborate with the Consortium to analyze data or specimens.

Advances are needed in the therapy of treatment-refractory chronic graft-vs.-host disease (GVHD). Prior experimental and clinical data suggest proteasome inhibition may have immunomodulatory activity relevant to GVHD. Carfilzomib is a specific, irreversible, next-generation proteasome inhibitor with extensive experience in the therapy of multiple myeloma. To explore the safety and activity of carfilzomib in advanced chronic GVHD, we conducted a pilot multi-center phase II trial through the Chronic GVHD Consortium. Carfilzomib was administered at 20 mg/m2 on day 1, and then 36mg/m2 on days 8 and 15 of a 28-day treatment cycle (cycle 1), and then 36 mg/m2 on days 1, 8, and 15 of a 28-day treatment cycle (cycles 2-6). The primary endpoint was 6 month treatment failure, a composite endpoint including death, relapse, and requirement for an additional line of systemic immune suppressive (IS) therapy. Considering a historical 6 month treatment failure rate of 44%, this 20 subject pilot trial allowed estimation of the 6 month treatment failure rate with a standard error of 10 percentage points. Secondary objectives included safety, physician- and NIH-based response rates, failure-free survival, and patient-reported outcomes. Key eligibility criteria included age ≥ 18, NIH Consensus defined chronic GVHD, and failure of at least one prior line of systemic IS therapy. A total of 20 subjects were enrolled at 4 institutions. Median age was 53 years. Median time from transplant to enrollment was 2.8 years (IQR 1.7-5), and from chronic GVHD onset to enrollment 1.5 years (IQR 0.5-3.7). Chronic GVHD was NIH moderate (30%) or severe (70%), predominantly classic (90% vs. overlap 10%), and involved multiple diverse organ sites. Prior lines of systemic therapy for chronic GVHD were ≤ 2 (n=6, 30%) or ≥ 3 (n=14, 70%). Doses were held primarily for infection (50% of total held doses); only 4 patients (20%) completed all planned 6 months of carfilzomib. SAEs occurred in 40% of subjects, and 7 deaths occurred among study participants occurring between 0.3-9 months after last carfilzomib dose (none attributed to carfilzomib). The 6 month treatment failure rate was not significantly improved vs. the historical benchmark (40% vs. 44%, p=0.36), figure 1. NIH response rates at 3, 6, and 12 months are presented in figure 2. Overall survival at 6 and 12 months was 79% and 58%. Failure-free survival at 12 months was 32%. These pilot phase II data suggest that carfilzomib therapy in this very advanced chronic GVHD population did not improve expected 6 month treatment failure rates achieved under conventional practices and is not recommended for further study for this indication.