310 A girl with pre-B acute lymphoblastic leukemia on maintenance therapy with hereditary complement-mediated thrombotic microangiopathy (aHUS)

A 3-year old girl suffering from acute lymphoblastic leukemia (pre-B immunophenotype, medium risk, treatment protocol ALL IC-BFM 2009) during maintenance therapy (MTX 10mg/weekly/and 6-mercaptopurine 50mgm2 daily) had sudden onset of pallor, oliguria, and microhematuria (128 RBC/mm3). Initial complete blood count revealed normocytic anemia (Hb 59 g/L, Htc 16.3%, MCV 85.3 fL, platelets 26 x109/L) alongside elevated bilirubin (67 umol/L), urea (17.6 umol/L), creatinine (82 umol/L) and LDH (2296 U/L) and a reduced haptoglobin level (0.03 g/L). Plasma-free hemoglobin was elevated (154 mg/L), as well as d-dimers (2.87 mg/L), antithrombin III (126.8%), and fibrinogen(6 g/L). Immunohematological analysis (direct and indirect Coombs test, antiplatelet antibodies) was negative. Hematological data: Hb level (45g/L), minimum platelets count (3x109/L), maximum LDH level units (704.8 U/L), schistocytes seen (no). Renal impairment: oliguria with macrohematuria, maximum serum creatinine (86 µmol/L), creatinine clearance (Schwartz formula) 23 ml/min/1.73m2. Evidence of infective causes: no (stools O157:H7, Shigella sp, VTEC, Streptococcus pneumoniae). Endomysial antibodies (EMA), ANCA, methylmalonic aciduria, hyperhomocysteinemia negative. Renal histology: not done Laboratory investigation: reduced ADAMS-13 activity (40%, reference range 67-150 %) with normal C3 (0.75 g/L), C4 (0.27 g/L). Factor H level was high (1248 mg/L, reference range 250-880 mg/L) with terminal pathway activation marker level markedly increased (1315 ng/mL, ref. range 110-252 ng/mL), supporting pathological overactivation of the complement system. Treatment: The girl was initially treated with fresh frozen plasma, periodic RBC transfusions, and single plasmapheresis. On the 2nd day of admission, she received a first eculizumab infusion (300 mg). After application, we noticed an immediate increase in platelets and reticulocytes with a decrease in free plasma hemoglobin and global renal function recovery. Moderate hypertension that occurred was treated with enalapril and amlodipine. The former maintenance therapy was immediately switched to cyclophosphamide. The girl is well, with continued eculizumab treatment on a recommended schedule. Genetic analysis: The patient was found to be homozygous for the CFH H3 haplotype (involving the rare alleles of c.-331C>T, Q672Q, and E936D polymorphisms) reported as a risk factor of aHUS. The patient was homozygous for the MCPggaac haplotype of the CD46 gene reported as a risk factor of developing aHUS.ConclusionA triggering factor for thrombotic microangiopathy was drug-mediated, causing complement activation on a predisposing genetic background. To our best knowledge, this is the third similar case found in literature, the first to receive eculizumab in such cases as well as following early onset of complement activation disease.