PTCy, abatacept, and a short course of tacrolimus for GVHD prevention after haploidentical transplantation.

Reducing the incidence of graft-versus-host disease (GVHD) after haploidentical hematopoietic stem cell transplantation (HSCT) is warranted. Posttransplant cyclophosphamide (PTCy) is the main agent used for GVHD prevention in this setting. It remains unknown whether costimulation blockade can be safely combined with PTCy and enhance its efficacy. We performed a phase 1b-2 clinical trial to examine the combination of PTCy, abatacept, and a short course of tacrolimus (CAST) after peripheral blood haploidentical HSCT. The primary end point was the incidence of grades 2-4 acute GVHD by day +120. The study enrolled 46 patients with a median age of 60 years (range, 18-74 years). The cumulative incidences of grades 2-4 and 3 or 4 acute GVHD were 17.4% (95% confidence interval [CI], 9.2-32.9) and 4.4% (95% CI, 1.1-17.1), respectively. With a median follow-up of 15.3 months, the cumulative incidence of 1-year treatment-related mortality was 4.4% (95% CI, 1.1-17.1). The estimated 1-year moderate-to-severe chronic GVHD rate, relapse rate, progression-free survival, overall survival, and GVHD- and relapse-free survival were 15.9% (95% CI, 8-31.7), 11.7% (95% CI, 5-27.2), 84.1% (95% CI, 73.8-95.7), 85.9% (95% CI, 75.9-97.2), and 66.1% (95% CI, 53.4-81.8), respectively. Toxicities were similar to those expected in patients receiving haploidentical HSCT. This clinical trial showed that the CAST regimen is safe and effective in reducing the rate of grades 2-4 acute GVHD after haploidentical peripheral blood HSCT. This trial was registered at www.clinicaltrials.gov as #NCT04503616.

Clinical and immune correlate results from a phase 1b study of the histone deacetylase inhibitor mocetinostat with ipilimumab and nivolumab in unresectable stage III/IV melanoma.

Checkpoint immunotherapies (CPIs) have improved outcomes for metastatic melanoma patients, with objective response rates to combination ipilimumab and nivolumab of ~58%. Preclinical data suggest that histone deacetylase (HDAC) inhibition enhances antitumor immune activity and may augment CPI. In a phase Ib open-label pilot trial (NCT03565406), patients with therapy-naive metastatic melanoma were treated with the class I/IV HDAC inhibitor mocetinostat orally three times a week in combination with nivolumab and ipilimumab every 3 weeks for 12 weeks followed by 12-week maintenance cycles of nivolumab every 2 weeks and mocetinostat at the same dose and schedule as induction. The endpoints of the trial were safety, definition of a recommended phase 2 dose, preliminary assessment of response, and correlative marker determination. Patient PBMC and serum samples collected at baseline and on-treatment were assessed by flow cytometry and Luminex assays for immune correlates. Ten patients were treated: nine with 70-mg and one with 50-mg mocetinostat. In the 70-mg cohort, eight patients had objective responses. The patient in the 50-mg cohort had an early progression of disease. All patients had grade 2 or higher toxicities, and six had grades 3 and 4 toxicities. Patient PBMC showed significant decreases in myeloid-derived suppressor cells and trends towards reduced anti-inflammatory monocyte phenotypes. Patient serum showed significant upregulation of granzyme A and TNF and trends towards increased granzyme B and IFNγ. Collectively, combining CPI and mocetinostat had favorable response rates but with high levels of toxicity. Assessment of immune correlates supports a shift away from immunosuppressive phenotypes towards enhanced immune responses.

A Prospective Trial to Compare Deep Inspiratory Breath Hold With Prone Breast Irradiation.

PURPOSE: To compare heart and lung doses for adjuvant whole breast irradiation (WBI) between radiation plans generated supine with deep inspiratory breath hold (S-DIBH) and prone with free-breathing (P-FB) and examine the effect of breast volume (BV) on dosimetric parameters. METHODS AND MATERIALS: Patients with left breast ductal carcinoma in situ or invasive cancer receiving adjuvant WBI were enrolled on a single-institutional prospective protocol. Patients were simulated S-DIBH and P-FB; plans were generated using both scans. Wilcoxon signed-rank and rank-sum tests were used to compare intrapatient differences between plans for the entire cohort and within BV groups defined by tertiles. RESULTS: Forty patients were enrolled. Thirty-four patients are included in the analysis owing to patient withdrawal or inability to hold breath. With WBI dose of 4005 to 4256 cGy, mean heart dose (MHD) was 80 cGy in S-DIBH and 77 cGy in P-FB (P = .08). Mean ipsilateral lung dose (MLD) was 453 cGy in S-DIBH and 45 cGy in P-FB (P < .0001). Mean and max left anterior descending artery doses were 251 cGy and 551 cGy in S-DIBH, respectively (P = .1), and 324 cGy and 993 cGy in P-FB, respectively (P = .3). Hot spot and separation were 109% and 22 cm in S-DIBH, respectively, and 107% and 16 cm in P-FB, respectively (P < .0001). For patients with smallest BV, S-DIBH improved MHD and left anterior descending artery doses; for those with largest BV, P-FB improved cardiac dosimetry. With increasing BV, there was an increasing advantage of P-FB for MHD (P = .05), and max (P = .03) and mean (P = .02) left anterior descending artery doses, and the reduction in MLD, hot spot, and separation with P-FB increased (P < .05). CONCLUSIONS: MHD did not differ between P-FB and S-DIBH, whereas MLD was significantly lower with P-FB. Analysis according to breast volume revealed improved cardiac dosimetry with S-DIBH for women with smallest BV and improved cardiac dosimetry with P-FB for women with larger BV, thereby providing a dosimetric rationale for using breast size to help determine the optimal positioning for WBI.

Serum albumin at 1 year predicts long-term renal outcome in lupus nephritis.

OBJECTIVES: The study aimed to determine if serum albumin at 12 months predicts long-term renal outcome at 48 months. Data from the NYU SAMPLE (Specimen and Matched Phenotype Linked Evaluation) Lupus Registry were used to compare the performance of albumin, anti-double-stranded DNA, C3/C4, proteinuria and haematuria. METHODS: 82 patients with SLE with data at time of renal biopsy, at 12 months and at a second visit, and up to 48 months were included. The significance of each biomarker as a predictor of an adverse renal outcome (ARO), defined as doubling of serum creatinine, as creatinine >4 mg/dL if initial >2.5 mg/dL or ESRD, was evaluated in univariate and exploratory multivariable Cox proportional hazards models. Hazard ratios (HRs) for ARO with 95% CIs were generated. The receiver operating characteristic (ROC) curves at 48 months were used to identify the optimal cut-off point for albumin and proteinuria to predict ARO. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for albumin and proteinuria. RESULTS: Serum albumin and proteinuria had statistically significant HRs for ARO (0.140 and 1.459, respectively). The model with both albumin and proteinuria indicated no additional independent contribution of proteinuria to albumin alone. The ROC curves identified cut-offs of 3.7 g/dL for albumin and 0.964 urine protein to creatinine ratio for proteinuria. Albumin had a sensitivity of 94%, specificity of 87%, PPV of 64% and NPV of 98%. CONCLUSIONS: This study demonstrates serum albumin >3.7 g/dL is a predictor of a favourable long-term renal outcome. These results support the inclusion of albumin as an outcome in lupus nephritis trials and treat-to-target guidelines.

Delivery of adjuvant chemotherapy among stage III colon cancer patients at a public versus private hospital in New York City.

PURPOSE: Prior studies of timeliness of adjuvant chemotherapy (AC) initiation in stage III colon cancer have suggested longer time to AC at public compared with private hospitals. Few studies have explored differences in AC completion. We investigated whether timely initiation and completion of AC differed between a public and private hospital, affiliated with the same academic institution in a large, urban setting. METHODS: We conducted a retrospective cohort study of stage III colon cancer patients who had surgery and AC at the same medical center between 2008 and 2015, either at its affiliated public hospital (n = 43) or private hospital (n = 79). We defined timely initiation as receiving AC within 60 days postoperatively, and completion as receiving ≥ 75% of planned AC. Univariate and stepwise multivariable logistic regressions were used to identify factors associated with AC delivery. RESULTS: Median number of days to AC was significantly greater among patients at the public (53, range 31-231) compared with the private hospital (43, range 25-105; p = 0.002). However, the percentage of patients with timely AC initiation did not differ substantially by hospital (74 vs 81%, p = 0.40). In multivariable analysis, age (OR 0.95/year, 95% CI 0.91-0.99) and laparoscopic versus open surgery (OR 5.65, 95% CI 1.92-16.62) were significant factors associated with timely AC initiation. Moreover, AC completion did not differ significantly between public (83.7%) and private (89.9%) hospital patients (p = 0.32). CONCLUSIONS: The proportions of patients with timely initiation and completion of AC were similar at a public and private hospital affiliated with a large, urban medical center. Future research should investigate how specific system-level factors help alleviate this expected difference in timely care delivery.