Sequential monitoring of minimal residual disease in acute lymphoblastic leukemia: 7-year experience in a pediatric hematology/oncology unit.

We evaluated minimal residual disease (MRD) in 91 children with acute lymphoblastic leukemia (ALL) by PCR amplification of clonal rearrangements, immunoglobulin (IgH; VDJ rearrangement, CDR3 region) and T-cell receptor (TCRdelta). Sequential monitoring of MRD was performed at different time points during and after chemotherapy and was correlated to patient outcome. In total, 792 bone marrow samples were assessed for MRD at the end of induction, and during and after treatment completion. MRD positivity at the end of induction was detected in 12% of patients and was associated with high incidence of relapse, 54.55% (p = 0.0002), at 5 years. On the other hand, 88% of patients were MRD-negative at the end of induction and the relapse rate at 5 years was very low, 5%. The frequency of MRD decreased to 16% in the first 6 months of chemotherapy; however, the incidence of relapse in MRD-positive patients remained high, 42.8%. After treatment completion (24-36 months from diagnosis), 32% patients were MRD-positive and the relapse rate was 36.5% (p = 0.0009). Our results indicated that monitoring of MRD constituted an essential prognostic marker, and detection of MRD particularly at the end of induction and after treatment completion was strongly predictive for patient outcome.

Enterovirus-associated hemophagocytic syndrome in children with malignancy: report of three cases and review of the literature.

Enteroviruses can cause severe manifestations in children with malignancy. Infection-associated hemophagocytic syndrome (IAHS) due to enterovirus is a rare entity in children. Patients with malignancy and IAHS due to enterovirus were retrospectively evaluated at the University of Athens' Hematology-Oncology pediatric unit within a 6-year period (2000-2006). IAHS occurred in three cases among 56 patients with documented enteroviral infection. The diagnosis of IAHS was confirmed by bone marrow aspiration and biopsy. Nested reverse transcriptase-polymerase chain reaction (RT-PCR), sequencing of the amplified alleles, and immunohistochemistry were performed to document the presence of enterovirus. The type of enterovirus was specified by indirect immunofluorescence assay. At the early phase of the disease, patients presented mild, non-specific viral symptoms, persistent unexplained fever, and pancytopenia. At the late phase, patients had more severe manifestations, such as persistent high fever, diarrhea, weight loss, hepatosplenomegaly, and hepatic dysfunction. The therapeutic approach consisted of supportive care, administration of immunoglobulin (400 mg/kg or 2 g/kg), and pleconaril. All patients had fatal outcome; two patients succumbed to multiorgan failure (MOF), while one patient succumbed to ventricular fibrillation. IAHS usually has fulminant course and leads to severe and life-threatening complications, such as liver failure and MOF. IAHS should always be included in the differential diagnosis of viral syndrome or unexplained fever. The therapeutic approach for IAHS should be administered as early as possible, before the progression to irreversible tissue damage. Early therapeutic intervention involving high doses of immunoglobulin might be beneficial for the patient's outcome.

Enteroviral infections in children with malignant disease: a 5-year study in a single institution.

OBJECTIVES: The clinical presentation, severity and outcome of enteroviral infections in children with malignancy were studied. METHODS: All cases of enteroviral infections in a University Pediatric Hematology-Oncology Unit were assessed, during a 5-year period. RT-PCR, immunohistochemistry and indirect immunofluorescence assay were performed to document the enteroviral infection and the type of virus. RESULTS: Fifty-five children had documented enteroviral infection among 104 patients evaluated for possible enteroviral infection. Severe manifestations occurred in 11/55 (20%) patients, such as encephalitis 5/55, cardiac involvement 3/55 (1/55 myocarditis, 1/55 dilated cardiomyopathy, 1/55 ventricular fibrillation) and infection associated hemophagocytic syndrome 3/55. Children with lymphoid malignancy had increased incidence of enteroviral infections (87%) compared to children with solid tumors (13%). All patients received supportive care, intravenous immunoglobulin (IVIG) (30/55 low dose 400 mg/kg or 25/55 high dose 2 gr/kg) and/or pleconaril (2/55). All patients who received high dose of IVIG developed early negative viral load. However, 4 of them succumbed. Infection related fatality rate was 14.5% (N=8). CONCLUSIONS: Enteroviruses caused more severe and lethal manifestations especially in children with lymphoid malignancy. The administration of high dose of IVIG was beneficial in viremia. Thus, the early therapeutic intervention with high dose of IVIG may improve the outcome.

Could intensified treatment in childhood acute lymphoblastic leukemia improve outcome independently of risk factors?

PURPOSE: Many risk-directed therapeutic protocols have been proposed in acute lymphoblastic leukemia (ALL). However, the relapse rates remain high. The effectiveness of each protocol depends on how quickly the clearance of blast cells is achieved. In an attempt to improve survival, by minimizing treatment toxicity and relapse rate, different therapeutic protocols were used every 3 yr in our Unit. PATIENTS AND METHODS: During 1991-2000, 132 children with ALL were diagnosed in our Unit. Modified and intensified NY II and BFM protocols, in three consecutive periods [(Hematology/Oncology Pediatric Department of the University of Athens) HOPDA-91, HOPDA-94, HOPDA-97] were used. RESULTS: At a median follow-up time of 96 months, the 8-year overall survival (OS) was 88% +/- 3%, whereas the event-free survival (EFS) was 85% +/- 3%. There was a significant increase of the 5-year EFS of the high-risk (HR) group through time (65% in HOPDA-91 vs. 80% in HOPDA-97), whereas EFS of the low risk (LR) group in HOPDA-97 was 96%. Five cases relapsed (3.8%), four of which underwent successful bone marrow transplantation. Fifteen children died (13 diagnosed by 1996, two in the last 4 yr). CONCLUSION: Modification of the protocols significantly improved survival in both HR and LR groups. The intensified regimen in the LR group did not increase the adverse toxic events, but on the contrary was extremely effective.

Outbreak of enteroviral infection in a pediatric hematology-oncology unit.

We review the clinical courses and outcomes of an outbreak of enteroviral infection that occurred in 5 children with acute lymphoblastic leukemia during a 2-month period in a hematology-oncology unit. Three patients presented with encephalitis and 2 with parotitis. Three of the 5 patients recovered uneventfully and 2 died, 1 of chronic encephalitis and 1 of acute brain stem encephalitis.