Belumosudil, an investigational oral selective inhibitor of Rho-associated coiled-coil–containing protein kinase 2 (ROCK2), reduces type 17 and follicular T helper cells via downregulation of STAT3 ...and enhances regulatory T cells via upregulation of STAT5. Belumosudil may effectively treat patients with chronic graft-versus-host disease (cGVHD), a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2 randomized multicenter registration study evaluated belumosudil 200 mg daily (n = 66) and 200 mg twice daily (n = 66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions, and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR for belumosudil 200 mg daily and 200 mg twice daily was 74% (95% confidence interval CI, 62-84) and 77% (95% CI, 65-87), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg daily and 200 mg twice daily was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil because of possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. This trial was registered at www.clinicaltrials.gov as #NCT03640481.
•Belumosudil, a selective ROCK2 inhibitor, was well tolerated in heavily pretreated subjects, with 44% continuing treatment beyond 1 year.•Belumosudil demonstrated efficacy in patients with SR cGVHD, with responses in all organs and after failure of ibrutinib/ruxolitinib.
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Objective
Prior research has shown that cancer survivors often report positive psychological changes from the experience of cancer, or posttraumatic growth (PTG). However, few studies have focused on ...PTG in cancer patients recovering from hematopoietic cell transplantation (HCT). The present study measured PTG at specific milestones during the year following HCT and investigated psychosocial and treatment‐related factors that may hinder or facilitate PTG.
Methods
Participants (N = 430) completed assessments of PTG, social support, and coping pre‐transplant. Posttraumatic growth was also assessed at 1, 3, 6, and 12 months post‐transplant. Information about treatment regimen and post‐transplant complications was ed from medical records. Mixed‐effects linear regression models were used to evaluate the extent to which pre‐transplant social support, coping approaches, treatment intensity, and post‐transplant complications predicted PTG.
Results
Compared to pre‐transplant, PTG scores were significantly higher at 6‐ and 12‐month post‐transplant. Greater pre‐transplant social support significantly predicted greater PTG across the assessment points. Use of emotional engagement coping strategies also strongly predicted post‐transplant PTG. Conversely, coping styles characterized by emotional avoidance generally were not predictive of PTG. No treatment‐related factors or post‐transplant complications were predictive of PTG.
Conclusions
Findings indicate that supportive social relationships and coping by engaging with difficult emotions may facilitate PTG following HCT. Moreover, these factors were more important than medical characteristics in explaining PTG. Findings may guide the development of interventions to enhance positive psychological outcomes after HCT.
Transplantation-related mortality (TRM) is a major barrier to the success of allogeneic hematopoietic cell transplantation (HCT).
We assessed changes in the incidence of TRM and overall survival from ...1985 through 2004 in 5,972 patients younger than age 50 years who received myeloablative conditioning and HCT for acute myeloid leukemia (AML) in first complete remission (CR1) or second complete remission (CR2).
Among HLA-matched sibling donor transplantation recipients, the relative risks (RRs) for TRM were 0.5 and 0.3 for 2000 to 2004 compared with those for 1985 to 1989 in patients in CR1 and CR2, respectively (P < .001). The RRs for all causes of mortality in the latter period were 0.73 (P = .001) and 0.60 (P = .005) for the CR1 and CR2 groups, respectively. Among unrelated donor transplantation recipients, the RRs for TRM were 0.73 (P = .095) and 0.58 (P < .001) for 2000 to 2004 compared with those in 1990 to 1994 in the CR1 and CR2 groups, respectively. Reductions in mortality were observed in the CR2 group (RR, 0.74; P = .03) but not in the CR1 group.
Our results suggest that innovations in transplantation care since the 1980s and 1990s have reduced the risk of TRM in patients undergoing allogeneic HCT for AML and that this reduction has been accompanied by improvements in overall survival.
•HCT recipients with elevated IL-6 and IL-10 have more severe depression symptoms.•Change in IL-6 and IL-10 correspond with change in depression within participants.•Relationships are strongest for ...neurovegetative symptoms of depression.
Increased synthesis and release of inflammatory signalling proteins is common among individuals with hematologic malignancies undergoing hematopoietic cell transplantation (HCT) due to intensive conditioning regimens and complications such as graft-versus-host-disease and infections. Prior research indicates that inflammatory responses can activate central nervous system pathways that evoke changes in mood. This study examined relationships between markers of inflammatory activity and depression symptoms following HCT. Individuals undergoing allogeneic (n = 84) and autologous (n = 155) HCT completed measures of depression symptoms pre-HCT and 1, 3, and 6 months post-HCT. Proinflammatory (IL-6, TNF-α) and regulatory (IL-10) cytokines were assessed by ELISA in peripheral blood plasma. Mixed-effects linear regression models indicated that patients with elevated IL-6 and IL-10 reported more severe depression symptoms at the post-HCT assessments. These findings were replicated when examining both allogeneic and autologous samples. Follow-up analyses clarified that relationships were strongest for neurovegetative, rather than cognitive or affective, symptoms of depression. These findings suggest that anti-inflammatory therapeutics targeting an inflammatory mediator of depression could improve quality of life of HCT recipients.
Vitamin D is a steroid hormone with a broad range of biological effects ranging from the classical role as a mediator of calcium and phosphate balance to cellular differentiation and immune ...modulation. These effects impact normal and dysfunctional hematopoietic and immune function, which may allow an avenue for improved treatment and support of patients suffering from hematologic disorders. In this review, we will summarize the role of vitamin D in normal hematopoiesis, discuss ways in which vitamin D may improve outcomes, and discuss a potential role of vitamin D for treating hematologic disorders and modulating the immune system to improve the outcome of allogeneic stem cell transplant.
Abstract
Background
Allogeneic hematopoietic cell transplantation (HCT) is a widely used treatment for hematologic cancers, with survival rates ranging from 25% to 78%. Known risk factors for chronic ...graft-versus-host disease (cGVHD), a serious and common long-term complication, disease relapse, and mortality following HCT have been identified, but much of the variability in HCT outcomes is unexplained. Biobehavioral symptoms including depression, sleep disruption, and fatigue are some of the most prevalent and distressing for patients; yet research on biobehavioral risk factors for HCT outcomes is limited. This study evaluated patient-reported depression, sleep disruption, and fatigue as risk factors for cGVHD, disease relapse, and mortality.
Methods
Adults receiving allogeneic HCT for a hematologic malignancy (N = 241) completed self-report measures of depression symptoms, sleep quality, and fatigue (severity, interference) pre-HCT and 100 days post-HCT. Clinical outcomes were monitored for up to 6 years.
Results
Cox proportional hazard models (2-tailed) adjusting for patient demographic and medical characteristics revealed that high pre-HCT sleep disruption (Pittsburgh Sleep Quality Index >9; hazard ratio HR = 2.74, 95% confidence interval CI = 1.27 to 5.92) and greater post-HCT fatigue interference (HR = 1.32, 95% CI = 1.05 to 1.66) uniquely predicted increased risk of mortality. Moderate pre-HCT sleep disruption (Pittsburgh Sleep Quality Index 6-9) predicted increased risk of relapse (HR = 1.99, 95% CI = 1.02 to 3.87). Biobehavioral symptoms did not predict cGVHD incidence.
Conclusions
Biobehavioral symptoms, particularly sleep disruption and fatigue interference, predicted an increased risk for 6-year relapse and mortality after HCT. Because these symptoms are amenable to treatment, they offer specific targets for intervention to improve HCT outcomes.
Purpose
Chronic graft-versus-host disease (cGVHD) is a common late complication of allogeneic hematopoietic cell transplantation (HCT). This study comprehensively evaluated physical and psychological ...function among individuals with cGVHD. Additional aims were to investigate relationships between disease severity and psychological and physical function, and to investigate patterns of psychological and physical function by disease site.
Method
Adults at least 6 months post allogeneic HCT were enrolled and either had cGVHD (
n
=59) or served as a reference sample of HCT survivors with no cGVHD history (
n
= 19). Participants completed self-report measures of depression, anxiety, fatigue, insomnia, pain, cognition, and sexual function and had a comprehensive clinical evaluation of cGVHD using NIH consensus scoring criteria. Participants with cGVHD were stratified by disease severity and site and compared to the reference group with no cGVHD.
Results
Participants with mild cGVHD had comparable psychological and physical symptoms to the reference sample, while participants with moderate cGVHD experienced more severe anxiety and problems with sexual function, and participants with severe cGVHD experienced more severe depressive symptoms and pain compared to the reference sample. Participants with cGVHD manifesting in the skin and GI tract had the most severe symptoms, including mood disturbance, fatigue, and pain.
Conclusions and Implications for Cancer Survivors
Results suggest that patients with more severe cGVHD and those with cGVHD manifesting in the skin, GI tract, and lungs are at risk for poorer psychological and physical outcomes and may benefit from proactive interventions to optimize function.
Highlight ► This review addresses pathways by which behavioral factors can influence immune processes relevant to the recovery following hematopoietic stem cell transplantation.
Abstract
Background
Mood disturbance, pain, and fatigue are prevalent and distressing concerns for patients with hematologic cancer recovering from hematopoietic stem cell transplantation (HSCT). The ...way in which individuals approach difficult thoughts and emotions may affect symptoms and functioning. Specifically, mindfulness has been associated with more optimal psychological and physical functioning, whereas experiential avoidance has been associated with poorer outcomes.
Purpose
The primary objective was to determine whether mindfulness and experiential avoidance measured prior to HSCT were associated with recovery of psychological and physical functioning following HSCT. We also evaluated dimensions of mindfulness to determine which were most robustly associated with outcomes.
Methods
Participants completed measures of mindfulness and experiential avoidance prior to HSCT. Depression and anxiety symptoms and pain and fatigue interference with daily activities were assessed prior to HSCT and 1, 3, and 6 months post-HSCT.
Results
Participants who reported better ability to describe their internal experiences and who were better able to act with awareness experienced less depression, anxiety, and fatigue interference following HSCT. Participants who were nonjudgmental and nonreactive toward thoughts and emotions experienced less depression and anxiety following HSCT, but these traits were not associated with pain or fatigue interference. Being a good observer of internal experiences was not associated with outcomes, nor was experiential avoidance.
Conclusions
Results suggest that most facets of mindfulness may optimize psychological functioning following HSCT, and the ability to describe one’s internal experience and to focus on the present moment may have a beneficial influence on physical functioning.
Individuals with cancer who reported taking a mindful approach to thoughts and emotions prior to stem cell transplantation experienced less depression, anxiety, and fatigue during their recovery from transplant.
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