Ibrutinib significantly inhibited Bruton's tyrosine kinase (BTK) phosphorylation,in-vitro proliferation and enhanced overall survival in a preclinical Burkitt lymphoma (BL) model.

Pediatric and adult patients with recurrent/refractory Burkitt lymphoma (BL) continue to have poor outcomes, emphasizing the need for newer therapeutic agents. Bruton's tyrosine kinase (BTK) is activated following B-cell receptor stimulation and in part regulates normal B-cell development. Ibrutinib, a selective and irreversible BTK inhibitor, has been efficacious in chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Waldenström's macroglobulinemia, and marginal zone lymphoma. In this study, we investigated the efficacy of ibrutinib alone and in selective adjuvant combinations against BL in-vitro and in a human BL xenografted immune-deficient NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mouse model. Our data demonstrated that phospho-BTK level was significantly reduced in BL cells treated with ibrutinib (p < 0.001). Moreover, we observed a significant decrease in cell proliferation as well as significant decrease in IC50 of ibrutinib in combination with dexamethasone, rituximab, obinutuzumab, carfilzomib, and doxorubicin (p < 0.001). In-vivo studies demonstrated ibrutinib treated mice had a significantly prolonged survival with median survival of mice following ibrutinib treatment (32 days) (24 days) (p < 0.02). In conclusion, our findings demonstrate the significant in-vitro and preclinical in-vivo effects of ibrutinib in BL. Based on our preclinical results in this investigation, there is an on-going clinical trial comparing overall survival in children and adolescents with relapsed/refractory BL treated with chemoimmunotherapy with or without ibrutinib (NCT02703272).

Autologous and allogeneic transplantation for burkitt lymphoma outcomes and changes in utilization: a report from the center for international blood and marrow transplant research.

Trends in utilization and outcomes after autologous or allogeneic hematopoietic cell transplantation (HCT) for Burkitt lymphoma were analyzed in 241 recipients reported to the Center for International Blood and Marrow Transplant Research between 1985 and 2007. The autologous HCT cohort had a higher proportion of chemotherapy-sensitive disease, peripheral blood grafts, and HCT in first complete remission (CR1). The use of autologous HCT has declined over time, with only 19% done after 2001. Overall survival at 5 years for the autologous cohort was 83% for those in CR1 and 31% for those not in CR1. Corresponding progression-free survival (PFS) was 78% and 27%, respectively. After allogeneic HCT, overall survival at 5 years was 53% and 20% for the CR1 and non-CR1 cohorts, whereas PFS was 50% and 19%, respectively. The most common cause of death was progressive lymphoma. Allogeneic HCT performed in a higher-risk subset (per National Comprehensive Cancer Network guidelines) resulted in a 5-year PFS of 27%. Autologous HCT resulted in a 5-year PFS of 44% in those undergoing transplantation in the second CR.

Myeloid hematopoietic growth factors and their role in prevention and/or treatment of neonatal sepsis.

Sepsis continues to be an important cause of morbidity and mortality among both full-term and preterm infants, secondary to an immaturity in neonatal host defense. The incidence of neonatal sepsis ranges from 30% in very low birth weight infants to 0.4% in preterm neonates and 0.1% in term neonates. The dysregulation of the expression and production of hematopoietic cytokines in the neonate contributes to quantitative and qualitative deficiencies in neonatal myeloid progenitor activity and decreased availability and function of mature effector neutrophils. These abnormalities contribute in large part to the increased incidence and mortality associated with neonatal sepsis. In this review, we have summarized and analyzed the studies investigating the dysregulation, expression and production of myelopoietic growth factors in neonates, the preclinical in vivo effects of myelopoietic growth factors in neonatal animals, the preclinical in vivo effects of myelopoietic growth factors during experimental sepsis in neonatal animals, the in vitro effects of growth factors on human neonatal phagocytic immunity, and clinical results of myelopoietic growth factors in human neonates. Future studies should be focused on investigating other abnormalities of neonatal host defense and multiple and simultaneous approaches to circumvent identified defects to attempt to reduce both the incidence and severity of neonatal host defense.