Background Prophylactic cranial irradiation has been a standard treatment in children with acute lymphoblastic leukemia (ALL) who are at high risk for central nervous system (CNS) relapse. Methods We conducted a clinical trial to test whether prophylactic cranial irradiation could be omitted from treatment in all children with newly diagnosed ALL. A total of 498 patients who could be evaluated were enrolled. Treatment intensity was based on presenting features and the level of minimal residual disease after remission-induction treatment. The duration of continuous complete remission in the 71 patients who previously would have received prophylactic cranial irradiation was compared with that of 56 historical controls who received it. Results The 5-year event-free and overall survival probabilities for all 498 patients were 85.6% (95% confidence interval [CI], 79.9 to 91.3) and 93.5% (95% CI, 89.8 to 97.2), respectively. The 5-year cumulative risk of isolated CNS relapse was 2.7% (95% CI, 1.1 to 4.3), and t...

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Treating childhood acute lymphoblastic leukemia without cranial irradiation.

Summary Background Genetic subtypes of acute lymphoblastic leukaemia (ALL) are used to determine risk and treatment in children. 25% of precursor B-ALL cases are genetically unclassified and have intermediate prognosis. We aimed to use a genome-wide study to improve prognostic classification of ALL in children. Methods We constructed a classifier based on gene expression in 190 children with newly diagnosed ALL (German Cooperative ALL [COALL] discovery cohort) by use of double-loop cross-validation and validated this in an independent cohort of 107 newly diagnosed patients (Dutch Childhood Oncology Group [DCOG] independent validation cohort). Hierarchical cluster analysis with classifying gene-probe sets revealed a new ALL subtype, the underlying genetic abnormalities of which were characterised by comparative genomic hybridisation-arrays and molecular cytogenetics. Findings Our classifier predicted ALL subtype with a median accuracy of 90·0% (IQR 88·3–91·7) in the discovery cohort and correctly identified 94 of 107 patients (accuracy 87·9%) in the independent validation cohort. Without our classifier, 44 children in the COALL cohort and 33 children in the DCOG cohort would have been classified as B-other. However, hierarchical clustering showed that many of these genetically unclassified cases clustered with BCR–ABL1 -positive cases: 30 (19%) of 154 children with precursor B-ALL in the COALL cohort and 14 (15%) of 92 children with precursor B-ALL in the DCOG cohort had this BCR–ABL1 -like disease. In the COALL cohort, these patients had unfavourable outcome (5-year disease-free survival 59·5%, 95% CI 37·1–81·9) compared with patients with other precursor B-ALL (84·4%, 76·8–92·1%; p=0·012), a prognosis similar to that of patients with BCR–ABL1 -positive ALL (51·9%, 23·1–80·6%). In the DCOG cohort, the prognosis of BCR–ABL1 -like disease (57·1%, 31·2–83·1%) was worse than that of other precursor B-ALL (79·2%, 70·2–88·3%; p=0.026), and similar to that of BCR–ABL1 -positive ALL (32·5%, 2·3–62·7%). 36 (82%) of the patients with BCR–ABL1 -like disease had deletions in genes involved in B-cell development, including IKZF1, TCF3, EBF1, PAX5, and VPREB1 ; only nine (36%) of 25 patients with B-other ALL had deletions in these genes (p=0·0002). Compared with other precursor B-ALL cells, BCR–ABL1 -like cells were 73 times more resistant to L-asparaginase (p=0·001) and 1·6 times more resistant to daunorubicin (p=0·017), but toxicity of prednisolone and vincristine did not differ. Interpretation New treatment strategies are needed to improve outcome for this newly identified high-risk subtype of ALL. Funding Dutch Cancer Society, Sophia Foundation for Medical Research, Paediatric Oncology Foundation Rotterdam, Centre of Medical Systems Biology of the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research, American National Institute of Health, American National Cancer Institute, and American Lebanese Syrian Associated Charities.

/pdf/a-subtype-of-childhood-acute-lymphoblastic-leukaemia-with-14npfbob80.pdf

A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study

https://www.zora.uzh.ch/id/eprint/40126/4/Conter_V_et_al_Molecular_response_in_AIEOP-BFM_ALL_2000_V.pdf

Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study

Asparaginases are a cornerstone of treatment protocols for acute lymphoblastic leukemia (ALL) and are used for remission induction and intensification treatment in all pediatric regimens and in the majority of adult treatment protocols. Extensive clinical data have shown that intensive asparaginase treatment improves clinical outcomes in childhood ALL. Three asparaginase preparations are available: the native asparaginase derived from Escherichia coli (E. coli asparaginase), a pegylated form of this enzyme (PEG-asparaginase), and a product isolated from Erwinia chrysanthemi, ie, Erwinia asparaginase. Clinical hypersensitivity reactions and silent inactivation due to antibodies against E. coli asparaginase, lead to inactivation of E. coli asparaginase in up to 60% of cases. Current treatment protocols include E. coli asparaginase or PEG-asparaginase for first-line treatment of ALL. Typically, patients exhibiting sensitivity to one formulation of asparaginase are switched to another to ensure they receive the most efficacious treatment regimen possible. Erwinia asparaginase is used as a second- or third-line treatment in European and US protocols. Despite the universal inclusion of asparaginase in such treatment protocols, debate on the optimal formulation and dosage of these agents continues. This article provides an overview of available evidence for optimal use of Erwinia asparaginase in the treatment of ALL.

L-asparaginase treatment in acute lymphoblastic leukemia: a focus on Erwinia asparaginase

Neuroblastoma is a type of cancer that most often affects children. Neuroblastoma occurs when immature nerve cells called neuroblasts become abnormal and multiply uncontrollably to form a tumor. Most commonly, the tumor originates in the nerve tissue of the adrenal gland located above each kidney. Other common sites for tumors to form include the nerve tissue in the abdomen, chest, neck, or pelvis. Neuroblastoma can spread (metastasize) to other parts of the body such as the bones, liver, or skin.

Neuroblastoma

https://www.zora.uzh.ch/id/eprint/33798/1/Moericke_Risk-adjusted_Therapy_in_ALL.pdf

Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95

From 1984 to 1989, 47 children with relapsed, refractory, and/or metastasized neuroblastoma were treated with 131I-metaiodobenzylguanidine (mIBG) in several different treatment combinations. At initial diagnosis, 36 children had Evans stage IV and 11 stage III disease. In 16 of the 47 children, tumor recurred after complete remission prior to mIBG treatment, 26 of 47 progressed from residual or nonresponding tumor, and in 5 of 47 tumor progression during chemotherapy was observed. Altogether the children were treated with a total of 112 courses (range 1-6) with a mean dosage of 8.9 +/- 6.7 mCi/kg body weight/treatment course. Total dose was 283.2 +/- 203.7 mCi for stage III and 388.9 +/- 218.6 mCi for stage IV. Nine of 47 children reached a complete or a very good partial remission (CR and VGPR) from mIBG treatment alone, 13 of 47 achieved partial remission (PR). In an early analysis, 10 patients treated with mIBG in the neuroblastoma trial NB 85 of the German Society of Pediatric Oncology showed no significant difference in survival time compared with 30 conventionally treated children. However, the recent therapy series has been done with higher doses of mIBG, and during improved therapeutic scanning many more bone lesions could be detected than during earlier diagnostic scanning. We conclude that mIBG treatment has not yet fulfilled the expectations for it but still seems for certain indications to be a promising tool to treat neuroblastoma in the future. Moreover, the frontier of neuroblastoma detection is still advancing.

Helmut Wehinger

Papers

Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95

Metaiodobenzylguanidine (mIBG) in treatment of 47 patients with neuroblastoma: results of the German Neuroblastoma Trial