High angiopoietin-2 and suppression of tumorigenicity-2 levels correlate with onset of sinusoidal obstructive syndrome—implication for the utility of serial biomarker monitoring

This longitudinal single-center study describes the timing and risk factors for genital human papillomavirus (HPV) disease in women after allogeneic hematopoietic cell transplantation (HCT). Between 1994 and 2014, 109 females underwent HCT of whom 82 surviving transplant for >1 year had regular, comprehensive genital tract assessment and treatment of HPV disease. The cumulative proportions of any genital HPV infection at 1, 3, 5, 10 and 20 years were 4.8%, 14.9%, 28.1%, 36.7% and 40.9%, respectively. Demographic, disease-related factors, chronic GvHD (cGvHD) and its treatment were analyzed for their association with persistent, multifocal or severe genital HPV disease. Pre-transplant HPV disease was strongly associated with any posttransplant HPV (odds ratio (OR)=6.5, 95% confidence interval (CI)=1.65–25.85, P=0.008). Having either extensive or genital cGvHD was associated with increased risk of any HPV disease (OR=5.7, 95% CI=1.90–17.16, P=0.002) and a higher risk for severe genital dysplasia (CIN II–III/VIN II–III; OR=13.1, 95% CI=1.59–108.26, P=0.017), but no one developed HPV-related genital cancer. Persistent, multifocal or severe HPV disease occurred more frequently than in healthy populations. Women with extensive cGvHD, genital cGvHD or pre-transplant HPV are at greatest risk for post-transplant HPV disease. Early initiation of annual screening, comprehensive genital tract assessment and active management are cornerstones of their gynecology care.

Accelerated bone mineral density loss (BMDL) occurs early after allogeneic stem cell transplantation (SCT) and is related to factors such as steroids and chronic GvHD. In order to understand the natural history of BMDL of SCT in the longer term, we evaluated a longitudinal cohort of 148 survivors with a median follow-up of 12 years (range 3–22 years). All women received hormone replacement therapy, and routine calcium/vitamin D supplementation was recommended but ∼50% of patients still had suboptimal vitamin D levels and bisphosphonates were rarely utilized. BMD significantly improved from 5 to 20+ years but the femoral neck and forearm remained vulnerable sites. Younger age, higher pretransplant body mass index (BMI) and increment in BMI post transplant were significantly associated with increased BMD and protected against osteopenia/osteoporosis. These findings support consideration of BMD loss in SCT survivors in two phases, an early phase of BMD loss (3–5 years) followed by a later phase of BMD recovery, with different protective and aggravating factors. Treatment- and transplant-related factors (such as steroids, immunosuppressives, chronic GvHD, vitamin D) are known to impact the early phase of BMD loss but age and BMI are more influential in the late phase of BMD recovery.

A major limitation to graft versus host disease (GVHD) research is that diagnosis relies on clinical symptoms and biopsy of the involved organs. Proteomic studies identified serum or plasma protein markers to predict the non-relapse mortality and acute GVHD. Especially ST2, Reg3α, TNFR1 are promising biomarkers to predict transplant outcomes in the multiple cohorts of allogeneic stem cell transplantation (allo-SCT), however gaps remain between biomarker discovery and its validation demanding a reliable and standardized assay format to measure GVHD biomarkers.

CD34+ dose significantly impacts transplant outcomes. Donor characteristics that impact CD34+ mobilization are particularly relevant in haploidentical transplantation, where there may be several eligible donors. A previous study in our institution (Vasu et. al, 2008) reported various predictors of CD34+ yield. We aimed to validate and further understand these predictors.

Neurocysticercosis, an infection of the central nervous system with the larval stage of the cestode Taenia solium, is common in developing countries but its occurrence and management in allogeneic hematopoietic stem cell transplantation (HSCT) has not been reported previously, to our knowledge. We report the case of an immigrant female patient who underwent a matched-related allogeneic HSCT for acute lymphoblastic leukemia and was incidentally found to have a solitary viable neurocysticercosis lesion. However, despite severe immunosuppression, the size of the cyst did not increase. More importantly, restoration of the immune system did not induce significant inflammation or seizures. Subsequent follow-up demonstrated complete resolution of the neurocysticercosis lesion. Thus, in the setting of HSCT, an asymptomatic patient with a single neurocysticercosis lesion was successfully managed without the use of anthelmintics, steroids, or anti-epileptics.

Clinical comorbidity measures enhance the estimates of HCT tolerance and outcomes, thereby aiding therapeutic decisions. Ex vivo T cell depletion (TCD) of the graft reduces the risk of graft-versus-host disease and improves the tolerability of allogeneic transplantation in patients with impaired pretransplant performance. However, prediction tools such as the hematopoietic cell transplantation-specific comorbidity index (HCT-CI), have only been validated in conventional T-replete HCT. To improve outcome prediction in TCD transplants we therefore evaluated published comorbidity measures and other potential biomarkers of outcome in a series of myeloablative TCD transplant recipients. Pre transplant (week -2) factors measured were: HCT-CI, ECOG performance status, serum C-reactive protein (CRP), albumin (ALB), pre-albumin (PAB), ferritin, absolute lymphocyte counts (ALC), and absolute lymphocyte / monocyte ratio (LMR). CRP was also studied serially post transplant. CRP increased after conditioning, peaked (p =0.0001) in the first week of HCT, with recovery to baseline at 5 weeks post-HCT. We evaluated outcomes in a cohort of 79 patients in our institute with hematological malignancies receiving myeloablative total-body irradiation, and an HLA-identical sibling peripheral blood HCT, T cell depleted using Miltenyi CD34+ selection. The median age of recipients was 43 years (range 13-68 years). Of the 79, 34 (43%) had standard risk disease, and 45 (57%) recipients had high-risk disease. At a median follow up of ∼ 5 years, overall survival (OS) was 42.9% and nonrelapse mortality (NRM) was 33.9%. Comorbidity measures were first screened to eliminate highly-correlated covariates. Univariate Cox regression models were used to identify significant factors (p 0 were found to be significantly associated with the cumulative incidence of relapse (both p=0.01). In conclusion, this is the first study to explore comorbidity scores and biomarkers to predict outcome after ex vivo TCD HCT. Our results suggest that HCT-CI score, preCRP, postCRP and the LMR are important independent clinical predictors of OS and NRM in TCD HCT. Disclosures: No relevant conflicts of interest to declare.