Background:
Even though children with acute myeloid leukemia (AML) receive a very intensive chemotherapy and most achieve a complete remission (CR) ~30% of patients suffer from relapse. ...Post-treatment monitoring of measurable residual disease (MRD) can allow detection of a re-emerging leukemic clone several months before clinical relapse, and studies are in progress that aim at treating children with a molecular relapse.
Specific genetic aberrations can be used for disease monitoring after therapy completion, but even though oncogenic fusion transcripts are more common in childhood than adult AML, NPM1 mutation is much rarer and consequently MRD measurements based on these aberrations are clinically applicable in only ~40% of childhood AML patients. Thus, a considerable fraction of patients do not have a suitable leukemia-specific molecular MRD target, but genes with an abnormally high expression in the leukemic cells might be candidate MRD targets in those patients. WT1 overexpression in childhood AML is well described, and if distinctly overexpressed at diagnosis, serves as a suitable MRD target in a large proportion of patients.
Gene expression profiling has identified several other genes with an abnormally high expression in the leukemic blasts compared to normal hematopoietic cells.
We investigated the applicability of 4 leukemia-associated genes (PRAME, GAGED2, ST18, SPAG6) as targets for early detection of relapse in peripheral blood (PB) in a Danish cohort of childhood AML patients, defined child-specific reference values of gene expression based on a large material of PB and BM samples from hematologically healthy children, and investigated gene expression levels under the presence of infection.
Methods:
We investigated the expression of 4 leukemia-associated genes (PRAME, GAGED2, ST18, SPAG6) in hematologically healthy children (n=53) and during suspected infection in febrile but otherwise healthy children (n=90). Gene expression in de novo AML at diagnosis (n=50) and during follow-up (n=20) was compared with child-specific reference values. We defined the 95th percentile of expression levels in hematologically healthy children as the upper limit of normal expression.
RT-qPCR analyses were performed in compliance with EAC protocols and due to concordant qPCR efficiencies the ΔΔCq method for relative quantification could be applied.
Results:
At AML diagnosis, 64% had high expression of at least 1 of the 4 genes defined as >20-fold overexpression compared to hematologically healthy children. Nine out of 10 patients (90%) without established molecular MRD targets or high WT1 expression had high expression of at least 1 of the 4 genes. All 7 children with t(9;11) had GAGED2>1000-fold overexpressed. Gene expression was quantified in 99 PB samples (163 RT-qPCR analyses) during follow-up in 20 patients with distinct overexpression at diagnosis. All 10 patients with PB sampling performed within 100 days of disease recurrence displayed expression above normal by a median of 1.6 months (range 0.5-6 months) before hematological relapse. Patients with CBF-AML had a significantly longer interval between molecular relapse and hematological relapse than patients with non-CBF-AML (2.5 months (range 0.8-6 months) vs. 0.9 months (range 0.5-2 months), p=0.047). One patient with PB sampling performed only once at 119 days prior to hematological relapse did not show any molecular evidence of disease recurrence before hematological relapse. Only 1 of 96 (1%) post-therapy follow-up analyses performed in 9 patients in continuous CR for >5 years after diagnosis had expression above normal. In this case, a 9-year-old girl in continuous CR had an increase in ST18 expression, however the increase was transient and returned to normal level in the following samples.
We found no clinically relevant influence of fever on gene expression levels, except for GAGED2, where 21% of febrile children had expression above normal.
Conclusions:
Sequential post-therapy monitoring of overexpressed genes in PB can predict relapse in childhood AML patients and facilitates molecular MRD monitoring in 90% of patients without a leukemia-specific target or WT1 overexpression. Frequent PB sampling (every 4-6 weeks) is necessary to detect an upcoming relapse, however in the post-treatment follow-up setting PB serves as an attractive and easily accessible source of preference compared to BM aspiration.
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No relevant conflicts of interest to declare.
Inborn hemolytic anemia requiring frequent blood transfusions can be a life-threatening disease. Treatment, besides blood transfusion, includes iron chelation for prevention of iron accumulation due ...to frequent blood transfusions. We present the results of a clinical investigation where the proband was diagnosed with severe hemolytic anemia of unknown origin soon after birth. Transfusion was required every 4–6 weeks. After whole exome sequencing of the proband and his parents as well as a healthy sibling, we established that the proband had a compound heterozygous state carrying two rare variants in the erythrocytic spectrin gene, SPTA1. The maternal allele was a stop mutation (rs755630903) and the paternal allele was a missense mutation (rs375506528). The healthy sibling had the paternal variant but not the maternal variant. These rare variants of SPTA1 most likely account for the hemolytic anemia. A severely reduced osmotic resistance in the erythrocytes from the proband was demonstrated. Splenectomy considerably improved the hemolytic anemia and obviated the need for blood transfusion despite the severe clinical presentation.
The reduced folate carrier (RFC) is involved in the transport of methotrexate (MTX) across the cell membrane. The RFC gene (SLC19A1) is located on chromosome 21, and we hypothesized that the RFC80 ...G>A polymorphism would affect outcome and toxicity in childhood leukemia and that this could interact with chromosome 21 copy number in the leukemic clone. A total of 500 children with acute lymphoblastic leukemia treated according to the common Nordic treatment protocols were included, and we found that the RFC AA variant was associated with a 50% better chance of staying in remission compared with GG or GA variants (P = .046). Increased copy numbers of chromosome 21 appear to improve outcome also in children with GA or GG variant. In a subset of 182 children receiving 608 high-dose MTX courses, we observed higher degree of bone marrow toxicity in patients with the RFC AA variant compared with GA/GG variants (platelet 73 vs 99/105 × 109/L, P = .004, hemoglobin 5.6 vs 5.9/6.0 mmol/L, P = .004) and a higher degree of liver toxicity in patients with RFC GG variant (alanine aminotransferase 167 vs 127/124 U/L, P = .05). In conclusion, the RFC 80G>A polymorphism interacts with chromosome 21 copy numbers and affects both efficacy and toxicity of MTX.
Treatment for pediatric acute myeloid leukemia is very toxic and the association between outcome and age and Body Mass Index is unclear. We investigated effect of age and Body Mass Index on toxicity ...and survival in pediatric acute myeloid leukemia. We studied all patients who completed first induction course of NOPHO-AML 2004 (n= 318). Toxicity following induction and consolidation courses (n= 6) was analyzed. The probabilities of toxicity and death were determined using time-to-event analyses with Cox multivariate proportional hazard regression for comparative analyses. Age 10-17 years was associated with sepsis with hypotension hazard ratio 2.3 (95% confidence interval 1.1-4.6). Being overweight (> 1 standard deviation) was associated with requiring supplemental oxygen 1.9 (1.0-3.5). The 5-year event-free and overall survival were 47% and 71%. Children aged 10-17 years showed a trend for inferior 5-year overall survival compared to children aged 29 (64% vs. 76%; P= 0.07). Infants showed a trend for superior 5-year event-free survival (66% vs. 43%; P= 0.06). Overweight children aged 10-17 years showed a trend for superior survival 5-year event-free survival 59% vs. 40% (P= 0.09) and 5-year overall survival 78% vs. 56% (P= 0.06) compared to healthy weight children aged 10-17 years. In conclusion, children aged 10-17 years and overweight children had a higher risk of grade 3-4 toxicity. Children aged 10-17 years showed inferior survival, but, unexpectedly, in this age group overweight children tended to have increased survival. This suggests different pharmacokinetics of chemotherapeutic drugs in adolescents and warrants further studies.
Purpose
Despite improved treatment and care, children and adolescents diagnosed with cancer continue to die, while many of those cured are burdened by treatment-related sequelae. The best clinical ...management of children and adolescents with cancer depends on healthcare professionals with various skills and expertise. Complex treatment, care and rehabilitation require collaboration between healthcare professionals. The purpose of this scoping review is to identify and evaluate existing interprofessional education in paediatric cancer.
Methods
We utilised the scoping review methodology and searched PubMed, Scopus and Education Resources Information Center. Inclusion criteria were postgraduate studies targeting more than one profession and evaluation of the educational intervention. We applied Kirkpatrick’s modified interprofessional education outcomes model to systematise outcomes.
Results
Of 418 references, nine studies fulfilled the inclusion criteria. The design, strategy and content of all the studies were heterogeneous. None of the interprofessional educations systematically evaluated knowledge, skills, attitudes or the effects on patient outcomes or quality of care.
Conclusion
There is a lack of well-structured, interprofessional education in paediatric cancer that has undergone evaluation. Paediatric cancer may benefit from systematic education and evaluation frameworks since interprofessional education could potentially strengthen the treatment, care and rehabilitation for children and adolescents with cancer.
We report a term male infant born to parents of Danish descent, who on the second day of life developed jaundice peaking at 67 hours and decreasing on applied double-sided phototherapy. In the weeks ...following, the infant showed signs of ongoing hemolysis. Laboratory tests showed very low glucose-6-phosphate dehydrogenase (G6PD) enzymatic activity, and sequencing of the G6PD gene revealed a previously uncharacterized missense mutation c. 592 C>A (Arg198Ser). Oral DNA from the infant had the same G6PD mutation, suggesting a spontaneous maternal germline mutation as the mutation was not observed in leukocytes from the mother.
Introduction
Chronic myeloid leukemia (CML) is rare in the first two decades of life comprising only 3% of newly diagnosed pediatric and adolescent leukemias. We studied the epidemiologic and ...clinical features of patients with CML diagnosed at younger than 3 years of age and evaluated treatment and long‐term outcome.
Method
Data from the International Pediatric I‐BFM/CML Registry were retrospectively analyzed using the European LeukemiaNet criteria of the year 2006. Characteristics and treatment outcome of patients <3 years old at diagnosis were evaluated from standardized forms.
Results
Twenty‐two patients (n = 22/479; 4.6%, male/female:14/8) were enrolled with a median age of 22 months (range, 10–34 m). Major symptoms comprised asthenia (30%), fever (30%), abdominal pain (20%), extramedullary signs (14%), hemorrhage (5%), and weight loss (5%). The extramedullary signs were specified in eight children: blueberry muffin (n = 1), sudden swollen abdomen (n = 1), sustained vomiting (n = 1), and cervical and inguinal lymph nodes (n = 5). Two of five children with cervical and inguinal lymph nodes were categorized as accelerated phase. Overall, 19 of 22 (86%) children were diagnosed in chronic phase, while the remaining three patients were in advanced phase. Median follow‐up was 78 months (range, 7–196 m). Twenty‐one out of 22 patients initially received imatinib, while one child received IFN + ARA‐C. Imatinib was changed to second‐line tyrosine kinase inhibitors (TKIs) in 29% of cases. During follow‐up, 41% patients underwent stem cell transplantation (SCT). While on TKI, major molecular response (MMR) was achieved in 48% of children. Among the remaining patients, 21% are alive on TKI without MMR and 22% achieved complete molecular response following SCT. Twenty‐one of 22 (95%) children are alive, while one patient died of posttransplant complications.
Conclusion
This report demonstrates for the first time the efficacy and long‐term effects of upfront imatinib in the so far largest cohort of children with CML diagnosed at very young age.
Summary
Given that 30–40% of children with acute myeloid leukaemia (AML) relapse after primary therapy it is important to define prognostic factors and identify optimal therapy. From 1993 to 2012, ...543 children from the Nordic countries were treated according to two consecutive protocols: 208 children relapsed. The influence of disease characteristics, first line treatment, relapse therapy and duration of first remission on outcome was analysed. Second complete remission (CR2) was achieved in 146 (70%) patients. Estimated 5‐year overall survival (OS5y) was 39 ± 4% for the whole group and 43 ± 4% for the 190 patients given re‐induction therapy, of whom 76% received regimens that included fludarabine, cytarabine (FLA) ± anthracyclines, 18% received Nordic Society for Paediatric Haematology and Oncology (NOPHO) upfront blocks and 5% received other regimens. Late relapse ≥1 year from diagnosis, no allogeneic stem cell transplantation (SCT) in first remission and core binding factor AML were independent favourable prognostic factors for survival. For the 128 children (124 in CR2) that received SCT as consolidation therapy after relapse, OS5y was 61 ± 5%. Four of 19 children (21%) survived without receiving SCT as part of relapse therapy. Our data show that intensive re‐induction followed by SCT can give cure rates of 40% in children with relapsed AML.
Overexpressed genes may be useful for monitoring of measurable residual disease (MRD) in patients with childhood acute myeloid leukemia (AML) without a leukemia-specific target. The normal expression ...of five leukemia-associated genes (SPAG6, ST18, MSLN, PRAME, XAGE1A) was defined in children without hematologic disease (n = 53) and children with suspected infection (n = 90). Gene expression at AML diagnosis (n=50) and during follow-up (n = 21) was compared with child-specific reference values. At diagnosis, 34/50 children (68%) had high expression of at least one of the five genes, and so did 16/31 children (52%) without a leukemia-specific target. Gene expression was quantified in 110 peripheral blood (PB) samples (median, five samples/patient; range, 1 to 10) during follow-up in 21 patients with high expression at diagnosis. All nine patients with PB sampling performed within 100 days of disease recurrence displayed overexpression of SPAG6, ST18, PRAME, or XAGE1A at a median of 2 months (range, 0.6 to 9.6 months) before hematologic relapse, whereas MSLN did not reach expression above normal prior to hematologic relapse. Only 1 of 130 (0.8%) follow-up analyses performed in 10 patients in continuous complete remission had transient expression above normal. SPAG6, ST18, PRAME, and XAGE1A expression in PB may predict relapse in childhood AML patients and facilitate MRD monitoring in most patients without a leukemia-specific target.
Hyperleucocytosis in paediatric acute myeloid leukaemia (AML) is associated with increased morbidity and mortality. We studied hyperleucocytosis in 890 patients with AML aged 0-18years registered in ...the Nordic Society of Paediatric Haematology and Oncology (NOPHO) registry, with special focus on very high white blood cell counts (WBC >200×10/l). Eighty-six patients (10%) had WBC 100-199×10(9) /l and 57 (6%) had WBC ≥200×10(9) /l. Patients with WBC ≥200×10(9) /l had a high frequency of t(9;11) and a paucity of trisomy 8. Due to the high frequency of deaths within the first 2weeks (30% vs. 1% for all others), overall survival in this group was inferior to patients with WBC <200×10(9) /l (39% vs. 61%). Main cause of early death was intracranial haemorrhage and leucostasis. Twenty-six per cent of these patients never started antileukaemic protocol therapy. Leukapheresis or exchange transfusion was used in 24% of patients with hyperleucocytosis without impact on survival. Patients with hyperleucocytosis surviving the first week had identical survival as patients with lower WBC. We conclude that death within the first days after diagnosis is the major challenge in patients with high WBC and advocate rapid initiation of intensive chemotherapy.
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