Post-Hematopoietic Cell Transplantation Relapsed Acute Lymphoblastic Leukemia: Current Challenges and Future Directions

Indumathy Varadarajan,1 Eric Pierce,1 Lisa Scheuing,1 Amy Morris,2 Firas El Chaer,1 Michael Keng1 1Department of Medicine, Division of Hematology and Oncology, University of Virginia, Charlottesville, VA, USA; 2Department of Pharmacy Services, University of Virginia, Charlottesville, VA, USACorrespondence: Michael Keng, Division of Hematology & Oncology, University of Virginia Comprehensive Cancer Center, West Complex Room 6009, 1300 Jefferson Park Ave, PO Box 800716, Charlottesville, VA, 22908, USA, Tel +1 434 924 4257, Fax +1 434- 243 6068, Email [email protected]: Allogeneic hematopoietic cell transplantation (allo-HCT) represents an important and potentially curative treatment option for adult patients with acute lymphoblastic leukemia. Relapse continues to remain the most important factor influencing overall survival post allo-HCT. We discuss early identification, clinical manifestations, and management of relapsed disease. Routine evaluation of measurable residual disease (MRD) and change in donor chimerism play a crucial role in early detection. Pivotal clinical trials have led to FDA approval of multiple novel agents like blinatumomab and inotuzumab. Combining targeted therapy with cellular immunotherapy serves as the backbone for prolonging overall survival in these patients. Donor lymphocyte infusions have traditionally been used in relapsed disease with suboptimal outcomes. This review provides insight into use of cellular therapy in MRD positivity and decreasing donor chimerism. It also discusses various modalities of combining cellular therapy with novel agents and discussing the impact of chimeric antigen receptor T-cell therapy in the setting of post allo–HCT relapse both as consolidative therapy and as a bridge to second transplant.Keywords: acute lymphoblastic leukemia, hematopoietic cell transplantation, relapsed disease, measurable residual disease, MRD, ALL, CART, DL

Ecosystem functions are resistant to extreme changes to rainfall regimes in a mesotrophic grassland

Aims: Major changes to rainfall regimes are predicted for the future but the effect of such changes on terrestrial ecosystem function is largely unknown. We created a rainfall manipulation experiment to investigate the effects of extreme changes in rainfall regimes on ecosystem functioning in a grassland system. Methods: We applied two rainfall regimes; a prolonged drought treatment (30 % reduction over spring and summer) and drought/downpour treatment (long periods of no rainfall interspersed with downpours), with an ambient control. Both rainfall manipulations included increased winter rainfall. We measured plant community composition, CO2 fluxes and soil nutrient availability. Results: Plant species richness and cover were lower in the drought/downpour treatment, and showed little recovery after the treatment ceased. Ecosystem processes were less affected, possibly due to winter rainfall additions buffering reduced summer rainfall, which saw relatively small soil moisture changes. However, soil extractable P and ecosystem respiration were significantly higher in rainfall change treatments than in the control. Conclusions: This grassland appears fairly resistant, in the short term, to even the more extreme rainfall changes that are predicted for the region, although prolonged study is needed to measure longer-term impacts. Differences in ecosystem responses between the two treatments emphasise the variety of ecosystem responses to changes in both the size and frequency of rainfall events. Given that model predictions are inconsistent there is therefore a need to assess ecosystem function under a range of potential climate change scenarios.</p