Intensive Supportive Care And Cytokines Promote Recovery Of Hematopoiesis After Total Body Irradiation (Tbi) Without Hematopoietic Stem Cell Support

Abstract Hematopoietic cells are highly sensitive to radiation damage and their loss after radiation exposure results in lethal infections. We asked if intensive supportive care and hematopoietic-specific cytokine treatment after doses of TBI that were previously identified as lethal would permit survival and promote recovery of endogenous hematopoiesis without requiring hematopoietic stem cell support in the well-established dog model. Historical results showed that after 4 Gy TBI and standard supportive care, only 1 of 28 dogs survived with recovery of endogenous hematopoiesis. The intensive supportive care regimen for dogs after irradiation included an antibiotic use algorithm for empiric treatment of prolonged neutropenia and fever. After TBI exposure, dogs were treated with an oral fluoroquinolone. If fever developed or when absolute neutrophil count (ANC) fell below 100/μL, dogs were empirically treated with the combination of intravenous ceftazidime and amikacin. Blood cultures were obtained with fevers, and antibiotics were adjusted based on culture results. If neutropenic fever persisted for 48 hours, additional empiric antibiotic treatment was added. Blood transfusion support included increased volume and frequency of irradiated blood products. Intravenous fluid support (10–30 mL/kg/day Lactated Ringer’s solution) was given until full clinical recovery. Intensive supportive care given to 60 dogs resulted in significantly improved survival after TBI compared to limited supportive care. With intensive supportive care, we observed high rates of survival in dogs following exposure of up to 7 Gy TBI with complete endogenous hematopoietic recovery (Table). Cytokine treatment consisting of either granulocyte colony stimulating factor (G-CSF) alone or combined G-CSF and fms-like tyrosine kinase 3 (flt-3) ligand (FL), given after TBI did not significantly improve long term survival compared to recipients of intensive supportive care alone, but it significantly decreased the duration of intensive and expensive supportive care. For all cohorts receiving cytokines after TBI, the recovery of ANC was more rapid compared with supportive care alone (p<0.002). Treatment with the combination of G-CSF (10 μg/kg/day) and FL (100 μg/kg/day), starting 2 hours after TBI and continuing until recovery of ANC>1000/μL resulted in more rapid recovery of ANC and platelets compared to G-CSF alone. Follow-up of all surviving dogs >6 months after irradiation showed sustained hematopoiesis and immune reconstitution. These studies show that in this model, hematopoietic stem cells survive doses of TBI up to 7 and 8 Gy without requiring infusion of either autologous or allogeneic hematopoietic stem cells, that intensive supportive care is sufficient to permit reliable survival after 7 Gy TBI, and that the cytokine combination of G-CSF and FL is more effective than G-CSF in promoting rapid recovery of neutrophils and platelets after moderately high dose TBI. The results are relevant for the treatment of victims of terrorist or accidental radiation exposure. TBI dose (Gy) Cytokine after TBI ANC Recovery Platelet Recovery Survival / total # of dogs studied survival at > day +120 Median Days after TBI 4 no 26 43 4/4 5 no 27 52 3/6 5 G-CSF 20 44 6/6 6 no 33 84 5/6 6 G-CSF 27 64 5/6 6 G-CSF + FL 18 53 5/5 7 no 55 77 5/6 7 G-CSF 24 64 5/5 7 G-CSF + FL 18 57 6/6 8 no* n/a n/a 0/4 8 G-CSF + FL 37 99 1/6