Elizabeth Shin

The association of adjuvant therapy with survival at the population level following pancreatic adenocarcinoma resection

BACKGROUND Using a retrospective observational cohort approach, the overall survival (OS) following curative-intent resection of pancreatic adenocarcinoma (PC) was defined at the population level according to adjuvant treatment, and predictors of OS were identified. METHODS Patients undergoing resection of PC in the province of Ontario between 2005 and 2010 were identified using the provincial cancer registry, and linked to databases that include all treatments received and outcomes experienced in the province. Pathology reports were abstracted for staging and margin status. Patients were identified as having received chemotherapy (CT), chemoradiation therapy (CRT), or no adjuvant treatment (NAT). Kaplan-Meier survival analysis of patients surviving ≥ 6 months was performed, and predictors of OS identified by log-rank test. Cox multivariable analysis was used to define independent predictors of OS. RESULTS Among the 473 patients undergoing PC resection, the median survival was 17.8 months; for the 397 who survived ≥ 6 months following surgery, the 5-year OS for the CT, CRT, and NAT groups was 21%, 16%, and 17%, respectively (p = 0.584). Lymph node-negative patients demonstrated improved OS associated with chemotherapy on multivariable analysis (HR = 2.20, 95% CI = 1.25-3.83 for NAT vs. CT). CONCLUSIONS Following PC resection, only patients with negative lymph nodes demonstrated improved OS associated with adjuvant chemotherapy.

Incidence, Risk Factors, and Long-Term Outcomes of Sclerotic Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation

Sclerotic chronic graft-versus-host disease (sclGVHD) is associated with significant morbidity and a poor quality of life. We reviewed 502 patients diagnosed with chronic GVHD and analyzed the incidence and risk factors of sclGVHD and long-term outcomes and immunosuppressive therapy (IST) cessation in patients with sclGVHD. With a median onset at 18 months the cumulative incidence of sclGVHD was estimated at 22.6% at 5 years (95% confidence interval, 18.6% to 26.8%). Univariate and multivariate analysis identified 2 risk factors for sclGVHD: non-T cell depletion (hazard ratio [HR] 9.09, P < .001) and peripheral blood stem cell (HR 3.87, P < .001). Overall survival (OS) at 5 years was significantly better in the sclGVHD group (88.1%) compared with the non-sclGVHD group (62.7%; P < .001), as were nonrelapse mortality (7.3% versus 21.5% at 5 years) and relapse rates (9.1% versus 19.3% at 5 years). There was no difference in the rate of IST cessation at 5 years (44.8% versus 49.9%, P = .312), but there was a trend of longer IST duration in the sclGVHD group compared with the non-sclGVHD group (median 71.6 months versus 62.9 months). In conclusion, T cell depletion and graft source affect the risk of sclGVHD. SclGVHD did not adversely affect long-term outcomes or IST duration.

Distinctive clinical characteristics and favorable outcomes in patients with large granular lymphocytosis after allo-HCT: 12-year follow-up data

An increase in large granular lymphocytes (LGL) is frequently seen in patients following allogeneic hematopoietic cell transplantation (allo‐HCT) and it has been associated with better outcomes in some reports. We assessed 826 consecutive patients at our institution with over 12 years of follow‐up for the occurrence of LGL lymphocytosis after allo‐HCT. The 3‐year cumulative incidence of LGL lymphocytosis was 14.5% with a median duration of over 3.5 years. The development of LGL lymphocytosis was strongly correlated with CMV viremia and GVHD. The clinical course of patients with LGL lymphocytosis after allo‐HCT was indolent, with the majority of these patients not displaying any clinical signs or symptoms related to the LGL proliferation. LGL lymphocytosis was associated with better outcomes, including higher overall survival (OS 86.6% vs 44.7% at 3 years), lower non‐relapse mortality (NRM 5.5% vs 30.4% at 3 years), and lower risk of relapse (8.9% vs 22.9% at 3 years). A time‐dependent multivariable analysis confirmed the favorable impact of LGL lymphocytosis on OS and NRM, but not on the risk of relapse. In multivariable analysis, a longer duration of LGL lymphocytosis was associated with better OS and NRM. Improved immunomodulatory properties of these cells, regulating GVHD and infections, may explain the observed favorable outcomes of patients who developed LGL lymphocytosis following allo‐HCT.

Therapeutic efficacy of azathioprine in addition to prednisone-based regimens as first-line chronic graft-versus-host disease treatment

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HCT) that is related to higher mortality and morbidity [1, 2]. Glucocorticoids has been the mainstay of the treatment for cGVHD, while it also has been widely used to treat the variety of autoimmune diseases as the combination with other immunosuppressive agents including azathioprine (AZP) to reduce long-term complications of glucocorticoids such as diabetes mellitus, iatrogenic Cushing’s syndrome, avascular necrosis of joints and osteoporosis, etc. [3–6]. Although a previous clinical trial suggested that prednisone (PRD) based regimen plus AZP (PRD+AZP) resulted in worse survival than PRD-based regimen in a standard risk group of cGVHD patients due to higher nonrelapse (infection-related) mortality (NRM) [7], the therapeutic efficacy of AZP might deserve to be looked at again because there have been advances in the allo-HCT field for over the last decades, including significant improvement in supportive care such as infectious prophylaxis and treatment, as well as in evaluating cGVHD systematically. The National Institutes of Health (NIH) first proposed consensus criteria for the diagnosis of cGVHD, and tools for scoring cGVHD organ involvement and assessing overall severity in 2005, which are now widely used in clinical practice [8, 9]. In addition, a new statistical endpoint for evaluating the efficacy of cGVHD treatment, i.e. failure free survival (FFS), has been introduced and suggested to be a potential surrogate of overall survival (OS) for cGVHD treatment [10, 11]. Therefore, we retrospectively reviewed 668 consecutive patients who underwent allo-HCT between 2004 and 2012 at Princess Margaret Cancer Centre, Toronto, Canada in order to compare the efficacy of PRD+AZP and PRD-based regimens with respect to FFS as well as OS, NRM, and the incidence of relapse. Chronic GVHD was defined, reclassified and graded by the NIH consensus criteria [8]. Among 313 patients with redefined cGVHD, we then identified 240 patients who received PRD or PRD+AZP as first line treatment for cGVHD. Late onset acute GVHD was excluded from the analysis. The FFS was defined as time from the initiation of frontline treatment for cGVHD to treatment failure (TF), NRM or relapse of disease. TF was defined as initiation of the next line of IST for cGVHD [11] or an escalation of the dose of PRD to ≥1 mg/kg/day regardless of the target organ. OS and FFS were calculated by the Kaplan–Meier method and compared using the log rank test. The cumulative incidences of NRM, disease relapse, and the TF rate (TFR) for front line cGVHD treatment were estimated considering competing risks, with disease relapse, NRM and TFR considered as mutually-competing risks. The transplant-related characteristics were analyzed to compare the PRD and PRD+AZP groups using Pearson’s Χ or Fisher’s exact test. The univariate and multivariate analyses performed to compare OS, NRM, relapse incidence, and FFS between two treatment groups. OS and FFS were compared using the log rank test. Univariate analyses for incidence with competing risks were performed by Gray’s method. Cox proportional hazard regression model was used for multivariate analysis of survivals. Since the characteristics of cGVHD of two treatment groups were imbalanced (Table 1), we performed a propensity score matching (PSM) analysis as a case-control study in order to adjust the potential confounding effects of the clinical features of cGVHD on treatment outcome. The * Dennis (Dong hwan) Kim dr.dennis.kim@uhn.ca