Conditioning Therapy by TBI and Etoposid Causing High Rate of Acute Kidney Injury in ALL Allogenetic Stem Cell Transplantation in Children

Results of children acute lymphoblastic leukemia (ALL) therapy improved dramatically in the past decades. Patients with very high risk leukemia may benefit from allogeneic hematopoieic stem cell transplantation (HSCT) after myeloablative conditioning regimen with expected overall survival of 70%. However such therapy could induce high toxicity such as acute kidney injury (AKI). In literature, up to 45% of children may experiment acute renal failure during HSCT. It could increase other toxicities and often leads to chronic kidney disease.

In this study we retrospectively reviewed medical files of patients treated at Robert Debré Hospital in Paris for very high risk ALL by allogenetic HSCT .

From March 2007 to January 2012, 57 consecutive patients were included. All patients received a myeloablative conditioning regimen followed by HSCT from either related or unrelated 9 and 10/10 HLA compatible donor or 4 to 6/6 cord blood. Patients received TBI in 6 fractions in 3 days from D-6 to D-3 and then etoposide (60mg/kg) at D-2 in 4 hour-infusion in central venous line. GvHD prophylaxis was cyclosporine A (CSA) 1.5mg/kg twice a day in 2-hour infusion alone for patients transplanted with sibling donor and CSA + short-course methotrexate and ATG for others.

From the 57 patients,  seven patients (14%) developed AKI  at day +1 from etoposid infusion (AKI group), defined by an increase of creatinine level of more than 2 fold of their own creatinine basis level and estimated glomerular filtration rate (EGFR) less than 90 ml/min/1.73m² the day after etoposide injection. Another group of 10 patients (17.5%) had a subclinical AKI with an increase between 1.5 and 2 fold (sAKI group). EGFR means before graft of the whole cohort was of 185.7ml/min/1.73m² [170-200]. At day +1 from etoposide infusion, AKI groupe patients eGFR mean was of 55.4 [33 -79] (p<0.0001) and  95.5 [72-118] (p<0.0155) ml/min/1.73m²respectively. Secondary to acute kidney injury, five patients among seven required a delay for stem cell injection. Two years overall survival at was of 84.4% [76.8-98] and was not statistically different between control, AKI and sAKI group. Relapse was similar in all groups (18.6% [42-3.8] for all patients). Transplanted related mortality was higher in AKI and sAKI groups versus control group. Indeed 3/17 patients with persistent complete remission died  in those 2 groups (TRM of 17.6% [0.4-50.6]), while no patient died in control group (p=0.007). Finally, GVH was of 62.8% [49.7;73.4] in control group, 85.7% [94.1;67.6] in AKI group and 80.6 [92.6;54.6] in sAKI group (p =NS).

Acute renal injury is frequent with TBI-VP16 based conditioning regimen for high risk ALL and occurs about 24 hours after etoposide injection. It is a major adverse effect, may impact mortality and delay transplantation. Long term consequence and chronic kidney disease should be evaluated among survivors. Further study are needed to specify these results.