Near-tetraploid T-cell acute lymphoblastic leukaemia in childhood: Results of the AIEOP-BFM ALL studies.

BACKGROUND: Near-tetraploidy-defined by DNA index 1.79-2.28 or 81-103 chromosomes-is a rare cytogenetic abnormality observed both in children and adults with T-cell acute lymphoblastic leukaemia (T-ALL) and its prognostic value is not yet determined. PATIENTS AND METHODS: We report a retrospective study conducted in paediatric patients with newly diagnosed T-ALL treated in AIEOP-BFM ALL 2000 and 2009 studies. 31 near-tetraploid T-ALL patients (1.4%) are compared to T-ALL patients without near-tetraploidy. RESULTS: Near-tetraploid karyotype was associated with lower frequency of high-risk features: white blood cells count at diagnosis ≥100,000/µL (19.3% versus 41.0%, p-value < 0.001), PPR (13.3% versus 35.8%, p-value = 0.01) and minimal residual disease high-risk at the end of consolidation phase Induction B (4.03% versus 14.6%, p-value = 0.001). Complete remission was achieved at the end of induction phase (day 33) in 100% near-tetraploid T-ALL patients, compared to 93.2% T-ALL without near-tetraploidy. CONCLUSION: Overall, we found that near-tetraploid T-ALL in newly diagnosed paediatric patients is associated with low-risk presenting features, with favourable treatment response and outcome.

Outcomes of paediatric patients with B-cell acute lymphocytic leukaemia with ABL-class fusion in the pre-tyrosine-kinase inhibitor era: a multicentre, retrospective, cohort study.

BACKGROUND: ABL-class fusion genes other than BCR-ABL1 have been identified in approximately 3% of children with newly diagnosed acute lymphocytic leukaemia, and studies suggest that leukaemic cells carrying ABL-class fusions can be targeted successfully by tyrosine-kinase inhibitors. We aimed to establish the baseline characteristics and outcomes of paediatric patients with ABL-class fusion B-cell acute lymphocytic leukaemia in the pre-tyrosine-kinase inhibitor era. METHODS: This multicentre, retrospective, cohort study included paediatric patients (aged 1-18 years) with newly diagnosed ABL-class fusion (ABL1 fusion-positive, ABL2 fusion-positive, CSF1R fusion-positive, and PDGFRB fusion-positive) B-cell acute lymphocytic leukaemia enrolled in clinical trials of multidrug chemotherapy done between Oct 3, 2000, and Aug 28, 2018, in which tyrosine-kinase inhibitors had not been given as a first-line treatment. Patients from 14 European, North American, and Asia-Pacific study groups of the Ponte di Legno group were included. No patients were excluded, and patients were followed up by individual study groups. Through the Ponte di Legno group, we collected data on the baseline characteristics of patients, including IKZF1, PAX5, and CDKN2A/B deletion status, and whether haematopoietic stem cell transplantation (HSCT) had been done, as well as treatment outcomes, including complete remission, no response, relapse, early death, and treatment-related mortality, response to prednisone, and minimal residual disease (MRD) at end of induction therapy. 5-year event-free survival and 5-year overall survival were estimated by use of Kaplan-Meier methods, and the 5-year cumulative incidence of relapse was calculated by use of a competing risk model. FINDINGS: We identified 122 paediatric patients with newly diagnosed ABL-class fusion B-cell acute lymphocytic leukaemia (77 from European study groups, 25 from North American study groups, and 20 from Asia-Pacific study groups). 64 (52%) of 122 patients were PDGFRB fusion-positive, 40 (33%) were ABL1 fusion-positive, ten (8%) were CSF1R fusion-positive, and eight (7%) were ABL2 fusion-positive. In all 122 patients, 5-year event-free survival was 59·1% (95% CI 50·5-69·1), 5-year overall survival was 76·1% (68·6-84·5), and the 5-year cumulative incidence of relapse was 31·0% (95% CI 22·4-40·1). MRD at the end of induction therapy was high (≥10-2 cells) in 61 (66%) of 93 patients, and most prevalent in patients with ABL2 fusions (six [86%] of 7 patients) and PDGFRB fusion-positive B-cell acute lymphocytic leukaemia (43 [88%] of 49 patients). MRD at the end of induction therapy of 10-2 cells or more was predictive of an unfavourable outcome (hazard ratio of event-free survival in patients with a MRD of ≥10-2vs those with a MRD of <10-2 3·33 [95% CI 1·46-7·56], p=0·0039). Of the 36 (30%) of 119 patients who relapsed, 25 (69%) relapsed within 3 years of diagnosis. The 5-year cumulative incidence of relapse in 41 patients who underwent HSCT (17·8% [95% CI 7·7-31·3]) was lower than in the 43 patients who did not undergo HSCT (45·1% [28·4-60·5], p=0·013), but event-free survival and overall survival did not differ between these two groups. INTERPRETATION: Children with ABL-class fusion B-cell acute lymphocytic leukaemia have poor outcomes when treated with regimens that do not contain a tyrosine-kinase inhibitor, despite the use of high-risk chemotherapy regimens and frequent HSCT upon first remission. Our findings provide a reference for evaluating the potential benefit of first-line tyrosine-kinase inhibitor treatment in patients with ABL-class fusion B-cell acute lymphocytic leukaemia. FUNDING: The Oncode Institute, Pediatric Cancer Foundation Rotterdam, Dutch Cancer Society, Kika Foundation, Deutsche Krebshilfe, Blood Cancer UK, Associazione Italiana per la Ricerca sul Cancro, Cancer Australia, National Cancer Institute, National Institute of Health, and St Baldrick's Foundation.

Therapeutic Drug Monitoring of Asparaginase Activity-Method Comparison of MAAT and AHA Test Used in the International AIEOP-BFM ALL 2009 Trial.

BACKGROUND: In the international AIEOP-BFM ALL 2009 trial, asparaginase (ASE) activity was monitored after each dose of pegylated Escherichia coli ASE (PEG-ASE). Two methods were used: the aspartic acid ß-hydroxamate (AHA) test and medac asparaginase activity test (MAAT). As the latter method overestimates PEG-ASE activity because it calibrates using E. coli ASE, method comparison was performed using samples from the AIEOP-BFM ALL 2009 trial. METHODS: PEG-ASE activities were determined using MAAT and AHA test in 2 sets of samples (first set: 630 samples and second set: 91 samples). Bland-Altman analysis was performed on ratios between MAAT and AHA tests. The mean difference between both methods, limits of agreement, and 95% confidence intervals were calculated and compared for all samples and samples grouped according to the calibration ranges of the MAAT and the AHA test. RESULTS: PEG-ASE activity determined using the MAAT was significantly higher than when determined using the AHA test (P < 0.001; Wilcoxon signed-rank test). Within the calibration range of the MAAT (30-600 U/L), PEG-ASE activities determined using the MAAT were on average 23% higher than PEG-ASE activities determined using the AHA test. This complies with the mean difference reported in the MAAT manual. With PEG-ASE activities >600 U/L, the discrepancies between MAAT and AHA test increased. Above the calibration range of the MAAT (>600 U/L) and the AHA test (>1000 U/L), a mean difference of 42% was determined. Because more than 70% of samples had PEG-ASE activities >600 U/L and required additional sample dilution, an overall mean difference of 37% was calculated for all samples (37% for the first and 34% for the second set). CONCLUSIONS: Comparison of the MAAT and AHA test for PEG-ASE activity confirmed a mean difference of 23% between MAAT and AHA test for PEG-ASE activities between 30 and 600 U/L. The discrepancy increased in samples with >600 U/L PEG-ASE activity, which will be especially relevant when evaluating high PEG-ASE activities in relation to toxicity, efficacy, and population pharmacokinetics.

Response of Symptomatic Persistent Chronic Disseminated Candidiasis to Corticosteroid Therapy in Immunosuppressed Pediatric Patients: Case Study and Review of the Literature.

BACKGROUND: Chronic disseminated candidiasis (CDC) is a severe invasive fungal infection principally observed during neutrophil recovery in patients with acute leukemia treated with intensive chemotherapy. Its pathophysiology remains unclear. We describe the management of 6 children with symptomatic CDC who did not respond to antifungal therapy. METHODS: The databases of the hematology-oncology departments of 2 tertiary pediatric medical centers were searched for all patients diagnosed with CDC from 2003 to 2015, who responded to corticosteroids after failing antifungal therapy. Clinical, laboratory and radiologic data were collected. RESULTS: Six patients (3 women, 3 men; 9-18 years of age) met the study criteria. Underlying diseases were acute lymphoblastic leukemia (n = 3) and large B-cell lymphoma, acute myeloid leukemia and severe aplastic anemia (n = 1 each). Presenting symptoms/signs of CDC were fever in all cases, with abdominal or chest pain, and/or mucositis. Candida infection was identified in blood cultures in 4 patients and in bronchoalveolar lavage fluid in one. In the absence of response to antifungal agents (4-50 days from CDC diagnosis), prednisone 2 mg/kg/day or equivalent was administered. CDC-attributable clinical symptoms resolved in 4 patients within 6-19 days; one patient required an additional nonsteroidal anti-inflammatory agent. Abnormalities on imaging decreased or disappeared within 5 months to 2 years in 4 patients. CONCLUSIONS: In children with persistent symptomatic CDC, despite adequate antifungal therapy, administration of corticosteroids may yield rapid resolution of symptoms and decreased inflammatory markers. In patients who do not respond to steroids, the addition of a nonsteroidal anti-inflammatory drug should be considered.