Kelly Corbet

Plasma microRNA signature as a noninvasive biomarker for acute graft-versus-host disease

Acute graft-versus-host disease (aGVHD) is the leading cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Approximately 35% to 50% of HCT recipients develop aGVHD; however, there are no validated diagnostic and predictive blood biomarkers for aGVHD in clinical use. Here, we show that plasma samples from aGVHD patients have a distinct microRNA (miRNA) expression profile. We found that 6 miRNAs (miR-423, miR-199a-3p, miR-93*, miR-377, miR-155, and miR-30a) were significantly upregulated in the plasma of aGVHD patients (n = 116) when compared with non-GVHD patients (n = 52) in training and validation phases. We have developed a model including 4 miRNAs (miR-423, miR-199a-3p, miR-93*, and miR-377) that can predict the probability of aGVHD with an area under the curve of 0.80. Moreover, these elevated miRNAs were detected before the onset of aGVHD (median = 16 days before diagnosis). In addition, the levels of these miRNAs were positively associated with aGVHD severity, and high expression of the miRNA panel was associated with poor overall survival. Furthermore, the miRNA signature for aGVHD was not detected in the plasma of lung transplant or nontransplant sepsis patients. Our results have identified a specific plasma miRNA signature that may serve as an independent biomarker for the prediction, diagnosis, and prognosis of aGVHD.

Cyclophosphamide-Based Hematopoietic Stem Cell Mobilization Before Autologous Stem Cell Transplantation in Newly Diagnosed Multiple Myeloma

High‐dose cyclophosphamide (Cy) is frequently employed for peripheral blood mobilization of hematopoietic stem cells before high‐dose chemotherapy with autologous stem cell transplantation (ASCT) in multiple myeloma (MM). The benefit of mobilization with Cy over filgrastim (granulocyte colony‐stimulating factor; G‐CSF) alone is unclear. Between 2000 and 2008, 167 patients with newly diagnosed MM underwent single ASCT after melphalan conditioning at our institution. Seventy‐three patients were mobilized with G‐CSF alone, and 94 patients with Cy plus G‐CSF (Cy+G‐CSF). We retrospectively analyzed Cys impact on both toxicity and efficacy. Mobilization efficiency was augmented by Cy; a mean total of 12 versus 5.8 × 106 CD34+ cells/kg were collected from patients mobilized with Cy+G‐CSF versus G‐CSF, respectively, (P < 0.01), over a mean of 1.6 versus 2.2 days of peripheral blood apheresis (p = 0.001). Mobilization‐related toxicity was also, however, augmented by Cy; 14% of Cy+G‐CSF patients were hospitalized because of complications versus none receiving G‐CSF (P < 0.0001). Toxicity, including death, related to ASCT was similar between cohorts. Regarding long‐term outcomes, multivariate analysis revealed no difference for Cy+G‐CSF versus G‐CSF (hazard ratio 0.8 for event‐free survival [95% confidence interval {CI} 0.57–1.25] and 0.96 for overall survival [95% CI 0.61–1.54]). In summary, we show that mobilization with Cy increases toxicity without positively impacting long‐term outcomes in MM. Our findings place into question Cys benefit as a routine component of stem cell mobilization regimens in MM. Randomized trials are needed to elucidate the risks and benefits of Cy more definitively. J. Clin. Apheresis 30:176–182, 2015.

Universal Mask Usage for Reduction of Respiratory Viral Infections After Stem Cell Transplant: A Prospective Trial

Universal surgical mask usage by both patients and providers reduced the incidence of respiratory viral infections in patients following hematopoietic stem cell transplant, especially parainfluenza 3, in this single-site prospective study.

Transplantation of Ex Vivo Expanded Umbilical Cord Blood (NiCord) Decreases Early Infection and Hospitalization

Delayed hematopoietic recovery contributes to increased infection risk following umbilical cord blood (UCB) transplantation. In a Phase 1 study, adult recipients of UCB stem cells cultured ex vivo for 3 weeks with nicotinamide (NiCord) had earlier median neutrophil recovery compared with historical controls. To evaluate the impact of faster neutrophil recovery on clinically relevant early outcomes, we reviewed infection episodes and hospitalization during the first 100 days in an enlarged cohort of 18 NiCord recipients compared with 86 standard UCB recipients at our institution. The median time to neutrophil engraftment was shorter in NiCord recipients compared with standard UCB recipients (12.5 days versus 26 days; P < .001). Compared with standard UCB recipients, NiCord recipients had a significantly reduced risk for total infection (RR, 0.69; P = .01), grade 2-3 (moderate to severe) infection (RR, 0.36; P < .001), bacterial infection (RR, 0.39; P = .003), and grade 2-3 bacterial infection (RR, 0.21; P = .003) by Poisson regression analysis; this effect persisted after adjustment for age, disease stage, and grade II-IV acute GVHD. NiCord recipients also had significantly more time out of the hospital in the first 100 days post-transplantation after adjustment for age and Karnofsky Performance Status (69.9 days versus 49.7 days; P = .005). Overall, transplantation of NiCord was associated with faster neutrophil engraftment, fewer total and bacterial infections, and shorter hospitalization in the first 100 days compared with standard UCB transplantation. In conclusion, rapid hematopoietic recovery from an ex vivo expanded UCB transplantation approach is associated with early clinical benefit.

Efficacy and safety of high‐dose chemotherapy with autologous stem cell transplantation in senior versus younger adults with newly diagnosed multiple myeloma

We retrospectively studied 340 fit patients with multiple myeloma (MM) who underwent autologous stem cell transplantation (ASCT). We hypothesized that progression‐free survival (PFS) of older patients was non‐inferior to that of younger patients after ASCT. Our null hypothesis was that the PFS hazard ratio (HR) for a 5‐year increase in age was ≥1.05; the alternative (non‐inferiority) hypothesis was that the HR was ≤1. The observed HR was 0.94 (95% confidence interval [CI] 0.86‐1.03); since the CI upper bound was <1.05, we reject the null hypothesis and conclude that PFS in older patients was at least as good as in younger patients. We cannot reject an analogous null hypothesis for overall survival (HR 1.06 [95% CI 0.94‐1.19]), since the CI upper bound >1.05. Toxicity was similar across ages and transplant‐related mortality was minimal. 28% of subjects <65 versus 45% of those ≥65 received maintenance therapy. In summary, ASCT prolongs PFS equally well in older vs. younger adults. Although we cannot exclude maintenance as a confounder, these data support ASCT for fit seniors with MM.

Adult Umbilical Cord Blood Transplantation Using Myeloablative Thiotepa, Total Body Irradiation, and Fludarabine Conditioning

Treatment-related mortality (TRM) remains elevated in adult patients undergoing umbilical cord blood transplantation (UCBT), including an early rise in TRM suggestive of excessive toxicity associated with the standard myeloablative total body irradiation (TBI), fludarabine, and cyclophosphamide regimen. In an attempt to reduce regimen-related toxicity, we previously studied a modified myeloablative regimen with TBI (1350 cGy) and fludarabine (160 mg/m2); TRM was decreased, but neutrophil engraftment was suboptimal. Therefore, to improve engraftment while still minimizing regimen-related toxicity, we piloted a myeloablative regimen with the addition of thiotepa (10 mg/kg) to TBI and fludarabine conditioning. Thirty-one adult patients (median age, 46 years; range, 19 to 65) with hematologic malignancies (acute leukemia/myelodysplastic syndrome, 77%; lymphoid malignancy, 23%) underwent single (n = 1) or double (n = 30) UCBT from 2010 to 2015 at our institution. The cumulative incidence of neutrophil engraftment was 90% (95% confidence interval [CI], 70% to 97%) by 60 days, with a median time to engraftment of 21 days (95% CI, 19 to 26). The cumulative incidence of platelet engraftment was 77% (95% CI, 57% to 89%) by 100 days, with a median time to engraftment of 47 days (95% CI, 37 to 73). Cumulative incidences of grades II to IV and grades III to IV acute graft-versus-host disease (GVHD) at day 100 were 45% (95% CI, 27% to 62%) and 10% (95% CI, 2% to 23%), respectively. The overall incidence of chronic GVHD at 2 years was 40% (95% CI, 22% to 57%), with 17% of patients (95% CI, 6% to 33%) experiencing moderate to severe chronic GVHD by 2 years. TRM at 180 days was 13% (95% CI, 4% to 27%), at 1 year 24% (95% CI, 10% to 41%), and at 3 years 30% (95% CI, 13% to 49%). Relapse at 1 year was 13% (95% CI, 4% to 27%) and at 3 years 19% (95% CI, 6% to 38%). With a median follow-up of 35.5 months (95% CI, 12.7 to 52.2), disease-free and overall survival at 3 years were 51% (95% CI, 29% to 69%) and 57% (95% CI, 36% to 73%), respectively. This regimen represents a reasonable alternative to myeloablative conditioning with TBI, fludarabine, and cyclophosphamide and warrants further study.