[Show abstract][Hide abstract] ABSTRACT: Background:
Hematopoietic stem cell transplantation (HCT) survivors are less likely to mount a strong immune response to trivalent inactivated influenza vaccine (TIV) when compared to matched, healthy controls.
High-dose (HD) or standard-dose (SD) TIV was given to adult HCT subjects 18 years or older at least six months post-transplant. Subjects were randomized 2:1 to receive either the HD (60μg hemagglutinin [HA]/strain/dose) or the SD (15μg HA/strain/dose) TIV. Injection-site and systemic reactions were documented after each vaccination and immune responses were measured before and after each vaccination.
A total of 44 subjects were enrolled (25 in year 1 and 19 in year 2), with 15 in the SD group and 29 in the HD group. The median time to vaccination after transplantation was 7.9 months (range 6-106 months); median age was 50 years (range, 19.6-73 years); and 61% were male. No differences in demographic or lab data were noted between groups; however, the HD group had higher median baseline total IgG level (676 vs. 469 mg/dL, p=0.025). No differences in individual injection-site or systemic reactions were noted in the HD compared to the SD group; however, more events of any injection-site symptom combined were reported in the HD group. No serious adverse events were attributed to vaccination. Post-vaccination, the HD group had a higher percentage of individuals with titers >1:40 and a higher geometric mean titer (GMT) against the H3N2 strain compared to the SD group.
HD and SD TIV were found to be safe and well tolerated in adult HCT recipients. However, the HD group had higher frequency of injection-site reactions, but the majority of the reactions were mild and resolved.. The HD group had a higher percentage of individuals with post-vaccination titer >1:40 and GMT for H3N2 antigen, indicating better immunogenicity. These data support the need for a phase II immunogenicity trial in HCT recipients.
No preview · Article · Dec 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: Several distinct graft-versus-host disease (GVHD)-related syndromes have been defined by the NIH Consensus Conference. We enrolled a prospective cohort of 911 hematopoietic cell transplantation (HCT) recipients at 13 centers between March 2011 and May 2014 to evaluate four GVHD syndromes: late acute GVHD, chronic GVHD, bronchiolitis obliterans syndrome, and cutaneous sclerosis. The median age at HCT was 53.7 years. Most patients received peripheral blood stem cell transplant (81%) using a non myeloablative or reduced intensity conditioning (55%). Pediatric age group and use of bone marrow and umbilical cord blood were underrepresented in our cohort (<=11%). The cumulative incidence of late acute GVHD (late onset and recurrent) was 10% at a median of 5.5 months, chronic GVHD was 47% at a median of 7.4 months, bronchiolitis obliterans was 3% at a median of 12.2 months, and cutaneous sclerosis was 8% at a median onset of 14.0 months after HCT. Late acute GVHD and bronchiolitis obliterans had particularly high non-relapse mortality of 23% and 32% by 2 years after diagnosis. The probability of late acute- and chronic- GVHD-free, relapse-free survival at one and two years after HCT was 38% and 26%. This multi-center, prospective study confirms the high rate of late acute and chronic GVHD syndromes and supports the need for continuous close monitoring and development of more effective GVHD treatment strategies to improve HCT success.
No preview · Article · Nov 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: Purpose:
We hypothesized that FAM (inhaled Fluticasone, Azithromycin, and Montelukast) with a brief steroid pulse could avert progression of new-onset BOS.
We tested this in a phase II, single-arm, open label, multicenter study (NCT01307462).
Thirty-six patients were enrolled within 6 months of BOS diagnosis. The primary endpoint was treatment failure, defined as 10% or greater FEV1% decline at 3 months. At 3 months, 6% (2/36, 95% CI 1%-19%) had treatment failure (vs. 40% in historical controls, p<0.001). FAM was well tolerated. Steroid dose was reduced by 50% or more at 3 months in 48% of patients who could be evaluated (n=27). Patient-reported outcomes at 3 months were statistically significantly improved for SF-36 social functioning score and mental component score, FACT emotional well-being, and Lee symptom scores in lung, skin, mouth, and the overall summary score compared to enrollment (n=24). At 6 months, 36% had treatment failure (95% CI 21%-54%, n=13/36, with 6 documented failures, 7 missing pulmonary function tests). Overall survival was 97% (95% CI 84%-100%) at 6 months. These data suggest that FAM was well tolerated and that treatment with FAM and steroid pulse may halt pulmonary decline in new-onset BOS in the majority of patients and permit reductions in systemic steroid exposure, which collectively may improve quality of life. However, additional treatments are needed for progressive BOS despite FAM.
No preview · Article · Oct 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: Background
Although advances in sequencing technologies have popularized the use of microRNA (miRNA) sequencing (miRNA-seq) for the quantification of miRNA expression, questions remain concerning the optimal methodologies for analysis and utilization of the data. The construction of a miRNA sequencing library selects RNA by length rather than type. However, as we have previously described, miRNAs represent only a subset of the species obtained by size selection. Consequently, the libraries obtained for miRNA sequencing also contain a variety of additional species of small RNAs. This study looks at the prevalence of these other species obtained from bone marrow aspirate specimens and explores the predictive value of these small RNAs in the determination of response to therapy in myelodysplastic syndromes (MDS).
Paired pre and post treatment bone marrow aspirate specimens were obtained from patients with MDS who were treated with either azacytidine or decitabine (24 pre-treatment specimens, 23 post-treatment specimens) with 22 additional non-MDS control specimens. Total RNA was extracted from these specimens and submitted for next generation sequencing after an additional size exclusion step to enrich for small RNAs. The species of small RNAs were enumerated, single nucleotide variants (SNVs) identified, and finally the differential expression of tRNA-derived species (tDRs) in the specimens correlated with diseasestatus and response to therapy.
Using miRNA sequencing data generated from bone marrow aspirate samples of patients with known MDS (N = 47) and controls (N = 23), we demonstrated that transfer RNA (tRNA) fragments (specifically tRNA halves, tRHs) are one of the most common species of small RNA isolated from size selection. Using tRNA expression values extracted from miRNA sequencing data, we identified six tRNA fragments that are differentially expressed between MDS and normal samples. Using the elastic net method, we identified four tRNAs-derived small RNAs (tDRs) that together can explain 67 % of the variation in treatment response for MDS patients. Similar analysis of specifically mitochondrial tDRs (mt-tDRs) identified 13 mt-tDRs which distinguished disease status in the samples and a single mt-tDR which predited response. Finally, 14 SNVs within the tDRs were found in at least 20 % of the MDS samples and were not observed in any of the control specimens.
This study highlights the prevalence of tDRs in RNA-seq studies focused on small RNAs. The potential etiologies of these species, both technical and biologic, are discussed as well as important challenges in the interpretation of tDR data.
Our analysis results suggest that tRNA fragments can be accurately detected through miRNA sequencing data and that the expression of these species may be useful in the diagnosis of MDS and the prediction of response to therapy.
[Show abstract][Hide abstract] ABSTRACT: Acute graft-versus-host disease (GVHD) remains a leading cause of morbidity and non-relapse mortality following allogeneic hematopoietic cell transplantation. The clinical staging of GVHD varies greatly between transplant centers and is frequently not agreed upon by independent reviewers. The lack of standardized approaches to handle common sources of discrepancy in GVHD grading likely contributes to why promising GVHD treatments reported from single centers have failed to show benefit in randomized multi-center clinical trials. We developed guidelines through international expert consensus opinion to standardize the diagnosis and clinical staging of GVHD for use in a large international GVHD research consortium. During the first year of use, the guidance was following discussion of complex clinical phenotypes by experienced transplant physicians and data managers. These guidelines increase the uniformity of GVHD symptom capture which may improve the reproducibility of GVHD clinical trials after further prospective validation.
No preview · Article · Sep 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Cutaneous sclerosis (CS) occurs in 20% of patients with chronic graft-versus-host disease (GVHD) and can compromise mobility and quality of life.
We conducted a prospective, multi-center, randomized, two-arm phase II crossover trial of imatinib (200 mg daily) or rituximab (375 mg/m2 intravenously weekly x 4 doses, repeatable after 3 months) for treatment of CS diagnosed within 18 months (NCT01309997). The primary endpoint was significant clinical response (SCR) at 6 months, defined as quantitative improvement in skin sclerosis or joint range of motion. Treatment success was defined as SCR at 6 months without crossover, recurrent malignancy or death. Secondary end points included changes of B cell profiles in blood (BAFF levels and cellular subsets), patient-reported outcomes, and histopathology between responders and non-responders with each therapy.
SCR was observed in 9 of 35 (26%, 95% CI 13-43%) participants randomized to imatinib and 10 of 37 (27%, 95% CI 14-44%) randomized to rituximab. Six (17%, 95% CI 7-34%) patients in the imatinib arm and 5 (14%, 95% CI 5-29%) in the rituximab arm had treatment success. Higher percentages of activated B cells (CD27+) were seen at enrollment in rituximab-treated patients who had treatment success (p = 0.01), but not in imatinib-treated patients.
These results support the need for more effective therapies for CS and suggest that activated B cells define a subgroup of patients with CS who are more likely to respond to rituximab.
No preview · Article · Sep 2015 · Clinical Cancer Research
[Show abstract][Hide abstract] ABSTRACT: By the year 2020, potentially one-half a million hematopoietic cell transplant (HCT) recipients will need long-term follow-up care to address not only chronic GvHD but also multiple other late consequences of transplant. Despite this increase in patients, there will not be a concomitant increase in the HCT workforce. Thus, the future of long-term patient management will require a new 'next-generation' clinical model that utilizes technological solutions to make the care of the HCT patient efficient, safe and cost-effective. Guideline-based decision support will be embedded in clinical workflows. Documentation requirements will be reduced as automated data collection from electronic medical records (EMRs) will populate registries and provide feedback for a rapid learning health system. Interoperable EMRs will disseminate treatment protocols to multiple care providers in a distributed long-term clinic model, such that providers outside of the transplant center can provide services closer to the patient. Patients will increase their participatory role through patient portals and mobile devices. At Vanderbilt, we have responded to some of these future challenges by embedding guideline-based decision support, structuring clinical documentation and being early adopters of communication technology. This manuscript describes the current state of some of these innovations, and a vision for the future of the long-term transplant clinic.Bone Marrow Transplantation advance online publication, 14 September 2015; doi:10.1038/bmt.2015.210.
No preview · Article · Sep 2015 · Bone marrow transplantation
[Show abstract][Hide abstract] ABSTRACT: Patient-reported outcomes are receiving increased attention as the search for successful treatment agents of chronic graft versus host disease continues. There is currently an ongoing multicenter, prospective cohort study lead by the Chronic GVHD Consortium of patients with chronic graft versus host disease. This paper summarizes published findings to date reporting factors impacting quality of life, symptom burden, and physical functioning in this cohort. Middle age, versus younger or older age, is associated with worse quality of life, despite lower symptom burden. The presence of chronic graft versus host disease at study enrollment was associated with lower quality of life, and improvement in severity does not always change quality of life. Other factors negatively impacting quality of life include the presence of overlap syndrome, specific gastrointestinal and joint and fascia manifestations, and poorer functional status and exercise tolerance. Collecting valid and concise quality of life data is essential in developing treatment strategies for chronic graft versus host disease.
No preview · Article · Aug 2015 · Current Hematologic Malignancy Reports