Allogeneic Hematopoietic Cell Transplantation for Blastic Plasmacytoid Dendritic Cell Neoplasm: A CIBMTR Analysis

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes

Suppression of insulin feedback enhances the efficacy of PI3K inhibitors.

Mutations in PIK3CA, which encodes the p110α subunit of the insulin-activated phosphatidylinositol-3 kinase (PI3K), and loss of function mutations in PTEN, which encodes a phosphatase that degrades the phosphoinositide lipids generated by PI3K, are among the most frequent events in human cancers. However, pharmacological inhibition of PI3K has resulted in variable clinical responses, raising the possibility of an inherent mechanism of resistance to treatment. As p110α mediates virtually all cellular responses to insulin, targeted inhibition of this enzyme disrupts glucose metabolism in multiple tissues. For example, blocking insulin signalling promotes glycogen breakdown in the liver and prevents glucose uptake in the skeletal muscle and adipose tissue, resulting in transient hyperglycaemia within a few hours of PI3K inhibition. The effect is usually transient because compensatory insulin release from the pancreas (insulin feedback) restores normal glucose homeostasis. However, the hyperglycaemia may be exacerbated or prolonged in patients with any degree of insulin resistance and, in these cases, necessitates discontinuation of therapy. We hypothesized that insulin feedback induced by PI3K inhibitors may reactivate the PI3K-mTOR signalling axis in tumours, thereby compromising treatment effectiveness. Here we show, in several model tumours in mice, that systemic glucose-insulin feedback caused by targeted inhibition of this pathway is sufficient to activate PI3K signalling, even in the presence of PI3K inhibitors. This insulin feedback can be prevented using dietary or pharmaceutical approaches, which greatly enhance the efficacy/toxicity ratios of PI3K inhibitors. These findings have direct clinical implications for the multiple p110α inhibitors that are in clinical trials and provide a way to increase treatment efficacy for patients with many types of tumour

Allogeneic Hematopoietic Cell Transplantation for Blastic Plasmacytoid Dendritic Cell Neoplasm:a CIBMTR analysis

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with standard conventional chemotherapy. Small observational studies have shown that allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We conducted an analysis of 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007-2018 using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Results: Median follow up of survivors was 49 months (range 6-121). 5-year overall survival (OS), disease-free survival (DFS), relapse, and non-relapse (NRM) rates were 51.2% (95% confidence interval [95%CI]: 42.5-59.8%), 44.4% (95%CI: 36.2-52.8%), 32.2% (95%CI: 24.7-40.3%), and 23.3% (95%CI: 16.9-30.4%), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age =60 was predictive for inferior OS (hazard ratio [HR]= 2.16, 95% CI 1.35-3.46, p= 0.001), and higher NRM [HR= 2.19, 95% CI 1.13-4.22, p= 0.02]. Remission status at time of allo-HCT (CR2/PIF/Relapse vs CR1) was predictive of inferior OS [HR= 1.87, 95% CI 1.14-3.06, p= 0.01] and DFS [HR= 1.75, 95% CI 1.11-2.76, p= 0.02]. Use of myeloablative conditioning with total body irradiation (TBI) was predictive for improved DFS and reduced risk of relapse. Conclusion: Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, while myeloablative conditioning with TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes

Allogeneic Hematopoietic Cell Transplantation for Blastic Plasmacytoid Dendritic Cell Neoplasm: a CIBMTR analysis.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with standard conventional chemotherapy. Small observational studies have shown that allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We conducted an analysis of 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007-2018 using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Results: Median follow up of survivors was 49 months (range 6-121). 5-year overall survival (OS), disease-free survival (DFS), relapse, and non-relapse (NRM) rates were 51.2% (95% confidence interval [95%CI]: 42.5-59.8%), 44.4% (95%CI: 36.2-52.8%), 32.2% (95%CI: 24.7-40.3%), and 23.3% (95%CI: 16.9-30.4%), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age ≥60 was predictive for inferior OS (hazard ratio [HR]= 2.16, 95% CI 1.35-3.46, p= 0.001), and higher NRM [HR= 2.19, 95% CI 1.13-4.22, p= 0.02]. Remission status at time of allo-HCT (CR2/PIF/Relapse vs CR1) was predictive of inferior OS [HR= 1.87, 95% CI 1.14-3.06, p= 0.01] and DFS [HR= 1.75, 95% CI 1.11-2.76, p= 0.02]. Use of myeloablative conditioning with total body irradiation (TBI) was predictive for improved DFS and reduced risk of relapse. Conclusion: Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, while myeloablative conditioning with TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes