Peder Skov Wehner

The impact of CYP3A5*3 on risk and prognosis in childhood acute lymphoblastic leukemia.

Objectives:  Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood; however, little is known of the molecular etiology and environmental exposures causing the disease. Cytochrome P450 3A5 (CYP3A5) plays a crucial role in the catalytic oxidation of endogenous metabolites and toxic substances, including chemotherapeutic agents. The aim of this study was to investigate the role of a single‐nucleotide polymorphism (CYP3A5*3 6986A>G), which renders low enzyme activity, in the risk of developing ALL and in the outcome for children with ALL.

Gene dose effects of GSTM1, GSTT1 and GSTP1 polymorphisms on outcome in childhood acute lymphoblastic leukemia

Children with acute lymphoblastic leukemia (ALL) react very differently to chemotherapy. One explanation for this is inherited genetic variation. The glutathione S-transferase (GST) enzymes inactivate a number of chemotherapeutic drugs administered in childhood ALL therapy. Two multiplexing methods were applied for genotyping the GSTM1 and GSTT1 genes (distinguishing between 0, 1, or 2 gene copies) and the GSTP1 313 A>G polymorphism, simultaneously. A total of 263 childhood ALL patients were genotyped. No gene dose effect on outcome was demonstrated with either GST polymorphisms. Grouping of GSTM1 and GSTT1 into poor (0 or 1 gene copy)—and good metabolizers (at least 2 gene copies)—showed that the poor metabolizers had a trend toward a better outcome (event-free survival =91.8%) compared with the good metabolizers (event-free survival =83.2%). Similarly, in the adjusted analysis the good metabolizers demonstrated a 2.2-fold higher risk trend of experiencing an event (resistant disease or relapse) compared with the poor metabolizers (P=0.066; hazard ratio =2.248; 95% confidence interval, 0.948-5.327). In conclusion, our results suggest that the combined gene dose of GSTM1 and GSTT1 may influence outcome in childhood ALL.

Genome-wide analysis of cytogenetic aberrations in ETV6/RUNX1-positive childhood acute lymphoblastic leukaemia.

The chromosomal translocation t(12;21) resulting in the ETV6/RUNX1 fusion gene is the most frequent structural cytogenetic abnormality among patients with childhood acute lymphoblastic leukaemia (ALL). We investigated 62 ETV6/RUNX1‐positive childhood ALL patients by single nucleotide polymorphism array to explore acquired copy number alterations (CNAs) at diagnosis. The mean number of CNAs was 2·82 (range 0–14). Concordance with available G‐band karyotyping and comparative genomic hybridization was 93%. Based on three major protein‐protein complexes disrupted by these CNAs, patients could be categorized into four distinct subgroups, defined by different underlying biological mechanisms relevant to the aetiology of childhood ALL. When recurrent CNAs were evaluated by an oncogenetic tree analysis classifying their sequential order, the most common genetic aberrations (deletions of 6q, 9p, 13q and X, and gains of 10 and 21) seemed independent of each other. Finally, we identified the most common regions with recurrent gains and losses, which comprise microRNA clusters with known oncogenic or tumour‐suppressive roles. The present study sheds further light on the genetic diversity of ETV6/RUNX1‐positive childhood ALL, which may be important for understanding poor responses among this otherwise highly curable subset of ALL and lead to novel targeted treatment strategies.

Interphase fluorescent in situ hybridization deletion analysis of the 9p21 region and prognosis in childhood acute lymphoblastic leukaemia (ALL): results from a prospective analysis of 519 Nordic patients treated according to the NOPHO-ALL 2000 protocol

Interphase fluorescent in situ hybridization (FISH) was applied on diagnostic BM smears from 519 children with acute lymphoblastic leukaemia (ALL) in order to establish the frequency and prognostic importance of 9p21 deletion in children enrolled in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) – 2000 treatment protocol. Among the patients, 452 were diagnosed with B‐cell precursor (BCP)‐ALL and 66 with T‐ALL. A higher incidence of 9p21 deletions was found in T‐ALL (38%) compared to BCP‐ALL (15·7%). Homozygous deletions were found in 19·7% of T‐ALL and 4·0% of BCP‐ALL; hemizygous deletions were found in 18·2% and 11·7% respectively. In our series, 9p21 deletions were detected in all age groups with a steady rise in the frequency with age. There was no significant difference in outcome between cases with or without 9p21 deletion or between cases with hemi‐ or homozygous deletions of 9p21. In conclusion, in this large series of childhood ALL deletion of 9p21 was not associated with worse prognosis. However, interphase FISH deletion analysis of 9p21 could be used as a first step to detect unfavourable subtle cytogenetic aberrations such as the dic(9;20) rearrangement.

Genomic profiling of thousands of candidate polymorphisms predicts risk of relapse in 778 Danish and German childhood acute lymphoblastic leukemia patients

Childhood acute lymphoblastic leukemia survival approaches 90%. New strategies are needed to identify the 10–15% who evade cure. We applied targeted, sequencing-based genotyping of 25 000 to 34 000 preselected potentially clinically relevant single-nucleotide polymorphisms (SNPs) to identify host genome profiles associated with relapse risk in 352 patients from the Nordic ALL92/2000 protocols and 426 patients from the German Berlin–Frankfurt–Munster (BFM) ALL2000 protocol. Patients were enrolled between 1992 and 2008 (median follow-up: 7.6 years). Eleven cross-validated SNPs were significantly associated with risk of relapse across protocols. SNP and biologic pathway level analyses associated relapse risk with leukemia aggressiveness, glucocorticosteroid pharmacology/response and drug transport/metabolism pathways. Classification and regression tree analysis identified three distinct risk groups defined by end of induction residual leukemia, white blood cell count and variants in myeloperoxidase (MPO), estrogen receptor 1 (ESR1), lamin B1 (LMNB1) and matrix metalloproteinase-7 (MMP7) genes, ATP-binding cassette transporters and glucocorticosteroid transcription regulation pathways. Relapse rates ranged from 4% (95% confidence interval (CI): 1.6–6.3%) for the best group (72% of patients) to 76% (95% CI: 41–90%) for the worst group (5% of patients, P<0.001). Validation of these findings and similar approaches to identify SNPs associated with toxicities may allow future individualized relapse and toxicity risk-based treatments adaptation.

Extended duration of prehydration does not prevent nephrotoxicity or delayed drug elimination in high-dose methotrexate infusions: A prospectively randomized cross-over study

Alkalized hydration is used as supportive care to prevent renal toxicity during infusions with high‐dose methotrexate (HDMTX). In children with acute lymphoblastic leukemia (ALL), the hydration is commonly initiated 4 hours before start of the methotrexate (MTX) infusion. To test if longer duration of prehydration would prevent MTX‐induced renal toxicity, we preformed a randomized cross‐over study comparing 12–4 hours of hydration before the infusion of HDMTX.

Palonosetron for the prevention of nausea and vomiting in children with acute lymphoblastic leukemia treated with high dose methotrexate

High dose methotrexate (HD‐MTX), used in the treatment of children with acute lymphoblastic leukemia (ALL), is moderately emetogenic. First generation 5‐HT3 receptor antagonists are effective prophylactic agents but require multiple administrations. Palonosetron has a half life of 36–42 hours and has higher affinity and selectivity to the 5‐HT3 receptor. Adult studies have demonstrated that palonosetron is both more effective and require fewer administrations than first generation 5‐HT3 receptor antagonists. The purpose of this study was to examine the effect of a single dose of palonosetron (5 µg/kg) for the prevention of chemotherapy‐induced nausea and vomiting in children 18 years of age with ALL treated with HD‐MTX, 5 g/m2.

Individualized toxicity-titrated 6-mercaptopurine increments during high-dose methotrexate consolidation treatment of lower risk childhood acute lymphoblastic leukaemia. A Nordic Society of Paediatric Haematology and Oncology (NOPHO) pilot study.

This study explored the feasibility and toxicity of individualized toxicity‐titrated 6‐mercaptopurine (6MP) dose increments during post‐remission treatment with High‐dose methotrexate (HDM) (5000 mg/m2, ×3) in 38 patients with Childhood (ALL). Patients were increased in steps of 25 mg 6MP/m2 per day if they did not develop myelotoxicity within 2 weeks after HDM. 6MP could be increased in 31 patients (81%). Toxicity was acceptable and did not differ significantly between groups. Patients receiving 75 mg/m2 per day had significantly shorter duration of treatment interruptions of 6MP than the remaining patients (P = 0·03). This study shows individualized toxicity‐titrated 6MP dosing during consolidation is feasible without increased risk of toxicity.

Immunophenotype-defined sub-populations are common at diagnosis in childhood B-cell precursor acute lymphoblastic leukemia

Immunophenotype-defined sub-populations are common at diagnosis in childhood B-cell precursor acute lymphoblastic leukemia

FAMily-Oriented Support (FAMOS): development and feasibility of a psychosocial intervention for families of childhood cancer survivors

Abstract Background: We developed and tested the feasibility of a manualized psychosocial intervention, FAMily-Oriented Support (FAMOS), a home-based psychosocial intervention for families of childhood cancer survivors. The aim of the intervention is to support families in adopting healthy strategies to cope with the psychological consequences of childhood cancer. The intervention is now being evaluated in a nationwide randomized controlled trial (RCT). Methods and design: FAMOS is based on principles of family systems therapy and cognitive behavioral therapy, and is delivered in six sessions at home. Families were recruited from all four pediatric oncology departments in Denmark after the end of intensive cancer treatment. We evaluated the feasibility of the intervention and of a RCT design for comparing the intervention with usual care. The evaluation was conducted among families enrolled in the study by tracking procedures and parents’ evaluations. Results: A total of 68 families (68 mothers, 60 fathers, 68 children with cancer and 73 siblings) were enrolled, with a participation rate of 62% of families. Fathers were highly represented (88% of families); also families with single parents (12%) and parents with basic education (7–12 years of primary, secondary, and grammar school education) were represented (12%). The dropout rate was 12% of families (all in the control group), and two families did not complete the intervention because of relapse. Evaluation by parents in the intervention group showed overall satisfaction with the format, timing, and content of the intervention. Conclusion: The results indicate that the FAMOS intervention is feasible in terms of recruitment, retention, and acceptability. The effects of the intervention on post-traumatic stress, depression, anxiety, family functioning, and quality of life will be reported after the nationwide RCT has been completed.