Transcriptomics,Genomics

Dataset Information

33

Differential gene expression profile correlates with bortezomib responsiveness in steroid-resistant cGVHD


ABSTRACT: Nineteen patients with steroid-refractory cGVHD (chronic graft versus host disease) received weekly bortezomib from 2 – 12 months (1.6 mg/m2 q wk x 4 followed by one week of rest). Treatment was well tolerated with no > grade 3 adverse events. Six patients achieved CR or good PR (gPR). Average Rodnan scores decreased from 22.6 ± 12.8 to 5.9 ± 6.2 (p<0.005) for 8 patients with sclerosis who completed > 2 treatments, including one patient with marked healing of suppurating lesions and significantly reduced chronic diarrhea in another. Thus, weekly bortezomib was safe and produced early improvements in some patients with longstanding refractory disease. CR or gPR correlated with a younger age and lower number of involved organs with a severity score of > 2. Based on gene expression array and pathway analyses, High Responders displayed an immune response profile that resembled that of hematopoietic stem cell-transplanted patients without cGVHD. By comparison, Low Responders showed markedly altered gene expressions in both cell-mediated immune response and proinflammatory pathways. Our preliminary findings suggest that bortezomib responsiveness may be predicated by distinct immunopathological manifestations among cGVHD patients. This trial was registered at www.clinicaltrials.gov as NCT01158105. Overall design: 54 total samples, 0 replicates, 8 healthy controls, 6 disease controls. Sample details follow. Eligible patients were 18 years or older with a confirmed clinical diagnosis of steroid-refractory cGVHD, defined as either failure to improve after 2 months or progression after 1 month of standard steroid-based therapy, and had no prior bortezomib treatment for cGVHD. Enrolled patients were required to be in remission from his/her primary malignancy for which HSCT was indicated, ECOG performance status < 3, life expectancy > 3 months, have not had myocardial infarction within 6 months prior to enrollment and not having received radiation therapy within 3 weeks, platelet count ≥ 50 x 10^9/L, absolute neutrophil count ≥ 1.0 x 10^9/L, total bilirubin ≤ 1.5x upper normal limit, creatinine clearance ≥ 30 mL/min and no peripheral neuropathy episodes (≥ Grade 2) within 14 days before enrollment. Patients with prior hypersensitivity to bortezomib, boron or mannitol were excluded from trial. Bortezomib was supplied in vials as open-label stock. Patients received Kytril premedication per institutional standards (1 mg intravenous/IV push) before start of VELCADE® (bortezomib; Millennium Pharmaceuticals) infusion (1.6 mg/m2). Bortezomib was administered on days 1, 8, 15, 22 of a 35-day cycle. Steroid dose that was in effect on Day 1 was maintained. All other agents given for GVHD treatment were withdrawn as tolerated. Patients with stable disease or better after two cycles continued for up to six cycles of bortezomib. Patients who continued to do well were eligible for up to six months of maintenance. Those patients continued on the same dose of bortezomib but on days 1 and 15 of a 28-day cycle. Followup after the final dose was for 6 months. Subjects were assessed for signs and symptoms of cGVHD on day 1 of each cycle by standardized criteria for cGVHD diagnosis, new clinical scoring system, and new guidelines for global assessment of cGVHD severity (NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD). Safety was assessed according to adverse event incidents for 30 days following the last dose for up to 6 months. Adverse events were recorded throughout the trial and followed by investigator until resolution. Enrolled patients also completed a neurotoxicity-directed questionnaire on presence and intensity of neuropathic pain and/or peripheral neuropathy from the patient's perspective. Responses were reviewed to assist with evaluation of onset and intensity of peripheral neuropathy and other neurotoxicities that may require intervention or dose modification. No change from baseline was considered as stable disease (SD). >50% improvement in any specific organ score or overall performance was considered partial response (PR). Disappearance of symptoms of cGVHD was considered complete response (CR). Worsening of symptoms in specific organ or overall observed in two consecutive assessment time points was considered as progressive disease (PD). All human subject-related study protocols were reviewed and approved by the institutional Review Board for Human Protection, Baylor University Medical Center. All patients signed informed consent before being enrolled into study. This trial was registered at www.clinicaltrials.gov as NCT01158105.

INSTRUMENT(S): Illumina HumanHT-12 V4.0 expression beadchip

SUBMITTER: Nicole Baldwin 

PROVIDER: GSE56495 | GEO | 2017-01-18

SECONDARY ACCESSION(S): PRJNA243507

REPOSITORIES: GEO

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