Genetic Associations with Immune-mediated Outcomes after Allogeneic Hematopoietic Cell Transplantation

Previous studies have identified more than 200 genetic variants associated with acute or chronic graft-versus-host disease (GVHD) or recurrent malignancy after allogeneic hematopoietic cell transplantation (HCT). We tested these candidate donor and recipient variants in a cohort of 4270 HCT recipients of European ancestry and in sub-cohorts of 1827 sibling and 1447 unrelated recipients who had 10/10 HLA-A, B, C, DRB1, DQB1-matched donors. We also carried out a genome-wide association study (GWAS) for these same outcomes. The discovery and replication analysis of candidate variants identified a group of closely linked recipient HLA-DPB1 single-nucleotide polymorphisms (SNPs) associated with an increased risk of acute GVHD and a corresponding decreased risk of recurrent malignancy after unrelated HCT. These results reflect correlation with the level of HLA-DPB1 expression previously shown to affect the risks of acute GVHD and relapse in unrelated recipients. Our GWAS identified an association of chronic GVHD with a locus of X-linked recipient intron variants in NHS, a gene that regulates actin remodeling and cell morphology. Evaluation of this association in a second replication cohort did not confirm the original replication results, and we did not reach any definitive conclusion regarding the validity of this discovery. The cohort used for our study is larger than those used in most previous HCT studies but is smaller than those typically used for other genotype-phenotype association studies. Genomic and disease data from our study are available for further analysis in combination with data from other cohorts.

Belumosudil for Patients with Chronic Graft-Versus-Host Disease: Combined Analysis of Failure-Free Survival (FFS) in the KD025-208 and Pivotal Rockstar Trials

ABSTRACT Introduction: Belumosudil (KD025) is a novel oral selective rho-associated coiled-coil-containing kinase-2 (ROCK2) inhibitor specifically designed for the treatment of cGVHD following an allogeneic hematopoietic cell transplant. It has been evaluated in the phase 2a dose-finding (KD025-208) and the pivotal phase 2 ROCKstar trials. Patients with cGVHD in the KD025-208 trial received belumosudil after failure of 1 to 3 prior systemic lines of therapy (LOTs), and those in the ROCKstar trial received belumosudil after failure of 2 to 5 prior systemic LOTs. The best overall response rate (95% CI) achieved, which was the primary end point, was 72% (64%-78%) across the 3 dosages (belumosudil 200 mg QD, 200 mg BID and 400 mg QD) that were studied across the 2 trials. This led to the recent FDA approval of the 200-mg QD dose for the treatment of adult and pediatric patients aged ≥12 years with cGVHD after failure of ≥2 prior systemic LOTs. FFS was a secondary end point in both trials. FFS is an established composite indicator for treatment success in cGVHD, as it incorporates recurrent malignancy, nonrelapse mortality (NRM) and the absence of subsequent cGVHD therapy. Historic rates of FFS in a prior large observational study of patients with cGVHD after second-line systemic therapy were 56% at 6 months, 45% at 12 months and 31% at 24 months (Inamoto, Blood 2013). Given limited data from contemporaneous clinical trials on FFS and prognostic factors of treatment failure, we studied pooled FFS and its determinants from the KD025-208 and ROCKstar trials. Methods: A total of 186 patients from the KD025-208 (n=54) and ROCKstar (n=132) trials treated with belumosudil 200 mg QD, 200 mg BID or 400 mg QD were analyzed . The median duration of belumosudil treatment was 9.9 months (range, 0.4-44.7 months). Prior therapies included tacrolimus (58%), sirolimus (46%), extracorporeal photopheresis (42%), mycophenolate mofetil (27%), ibrutinib (27%), ruxolitinib (21%) and cyclosporine (5%). Results: At enrollment, 70% of patients had severe cGVHD according to NIH global score, 52% had ≥4 organs involved and 37% received >3 prior LOTs. Overall, belumosudil was well tolerated, with drug discontinuations occurring in 10% of patients due to possible drug-related adverse events. The median FFS was 14 months. The estimated overall FFS (95% CI) rates were 75% (68%-81%), 54% (47%-61%) and 38% (29%-47%) at 6, 12 and 24 months, respectively (Table 1 and Figure). Reasons for failure included recurrent malignancy (6%), NRM (7%) and the addition of a new systemic cGVHD therapy (43%). Factors associated with increased risk of treatment failure (1-FFS) in both univariate and multivariate analyses (Table 2) included progressive onset of cGVHD (multivariate hazard ratio [HR]=2.1 [1.2-3.4]), absence of glucocorticoids in upfront therapy for cGVHD (HR=2.2 [1.2-4.0]) and ≥2 prior LOTs (HR=3.7 [1.2-12.2]). Conclusion: Treatment with belumosudil resulted in high FFS rates compared with historic benchmarks in cGVHD refractory to prior LOTs. Both NRM and relapse rates were low with the use of belumosudil. We identified distinct prognostic factors for FFS that can inform risk stratification and prognostication of patients being treated with belumosudil. Figure 1 Figure 1. Disclosures Lazaryan: Humanigen: Membership on an entity's Board of Directors or advisory committees; Avrobio: Membership on an entity's Board of Directors or advisory committees; Kadmon: Consultancy. Cutler: Mesoblast: Consultancy; Syndax: Consultancy; Omeros: Consultancy; Incyte: Consultancy; CareDx: Consultancy; Mallinckrodt: Consultancy; Pfizer: Consultancy; Kadmon: Consultancy; Editas: Consultancy; Cimeio: Consultancy; Deciphera: Consultancy; Jazz: Consultancy. Yang: Kadmon: Current Employment. Ieyoub: Kadmon: Current Employment. Eiznhamer: Kadmon: Current Employment. Blazar: BlueRock Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Carisma Therapeutics, Inc: Research Funding; Rheos Medicines: Research Funding; Tmunity Therapeutics: Other: Co-founder; Equilibre Pharmaceuticals Corp: Research Funding; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Lee: Amgen: Research Funding; Incyte: Research Funding; Novartis: Other: clinical trials, Research Funding; Pfizer: Research Funding; Kadmon: Research Funding; Takeda: Research Funding; Syndax: Research Funding; AstraZeneca: Research Funding; JANSSEN: Other; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees. Pavletic: Center for Cancer Research: Research Funding; National Cancer Institute: Research Funding; National Institutes of Health: Research Funding; Celgene: Research Funding; Actelion: Research Funding; Eli Lilly: Research Funding; Pharmacyclics: Research Funding; Kadmon: Research Funding.

The Role of Ultrasound-Guided Fine-Needle Aspiration of Thyroid Bed Lesions and Clinical Predictors of Recurrent Papillary Thyroid Carcinoma

Objectives Fine-needle aspiration (FNA) of thyroid bed lesions after thyroidectomy is challenging to evaluate. We determined the sensitivity, specificity, and positive and negative predicative value of thyroid bed FNA (TB-FNA) for detecting local recurrence of thyroid carcinoma. Methods A retrospective search was conducted for TB-FNAs from patients with a prior thyroid resection and subsequent ipsilateral FNA from the thyroid bed. Clinical and pathologic data were retrieved from the medical record. Patients were ultimately classified as “malignant” or “benign” based on the worst pathology identified and follow-up available. Results Forty-two cases were included, and the prior thyroidectomy pathology included 36 papillary thyroid carcinomas, two follicular carcinomas, one medullary carcinoma, and three benign cases. TB-FNA was adequate in 38 (90.5%) cases and interpreted as positive for malignancy (n = 22; 52.4%), suspicious for follicular neoplasm (n = 3; 7.1%), atypia of unknown significance (n = 2; 4.8%), and benign (n = 10; 23.8%). Twenty-seven patients had histologic follow-up, and 24 (87.5%) showed recurrent malignancy. The cytology sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 96%, 100%, 100%, 92.3%, and 97.4%, respectively, for identification of recurrent malignancy. Conclusions Most TB-FNA cases ultimately were diagnosed with malignancy on follow-up, although there may be sampling bias, as not all clinically benign cases had surgical follow-up.

Satisfaction of Search: Recurrent Wilms Tumor Mimicking Chest Port Granuloma on Chest Film

Wilms tumor (nephroblastoma) is the most common renal malignancy of childhood and typically presents as a painless abdominal mass. The high success rates of surgery and chemotherapy make recurrence of Wilms tumor uncommon. We report the case of a 5-year-old girl who underwent radical nephrectomy and chemotherapy for a Wilms tumor, but suffered a relapse of the tumor to the lung. The metastasis was initially detected as a density on chest radiograph that was, coincidentally, in the same location as a recently explanted chest port. The diagnosis of recurrent malignancy was thus obscured by the patient’s history as well as a correlating physical examination finding of a palpable mass at the site of the previously placed chest port. Moreover, the mass was not seen on lateral view, all of which suggested an alternative diagnosis of granulation tissue versus seroma rather than recurrent Wilms tumor. A high degree of clinical suspicion was necessary on the part of the clinician and radiologist to diagnose the relapse.

Salvage Endoscopic Full-Thickness Resection of Colorectal Carcinoma after Radiotherapy in a Patient Not Eligible for Surgery

For early, superficial colorectal carcinoma, endoscopic resection is an accepted curative treatment with an excellent long-term prognosis. Our report is the first report describing endoscopic full-thickness resection (eFTR) of residual recto-sigmoid carcinoma after radiotherapy. Our patient with cT2N0M0 recto-sigmoid carcinoma had been treated with radiotherapy because severe comorbidity precluded surgical resection. When the residual tumor was observed endoscopically, complete remission was achieved by endoscopic full thickness resection. There were no endoscopic or radiological signs of recurrent malignancy after the two-years follow-up period. In selected cases, eFTR after radiotherapy could be a curative treatment option.