Olafur G. Jonsson

Bone pain as an initial symptom of childhood acute lymphoblastic leukemia: Association with nearly normal hematologic indexes++

We reviewed the records of all patients with a diagnosis of ALL made at our center during a 13-year period to determine the relationship between bone pain and the hematologic findings at diagnosis of acute lymphoblastic leukemia. Of 296 eligible patients, 179 (60%) had no bone pain (group 1), 65 (22%) had some bone pain (group 2), and 52 (18%) had prominent bone pain that overshadowed other manifestations of the leukemia (group 3). Statistically significant differences were found between the groups for hemoglobin concentration (p less than 0.001), leukocyte count (p = 0.014), absolute neutrophil count (p = 0.002), percentage of circulating blast cells (p = 0.009), and platelet count (p less than 0.001). Children in group 3 had values closer to normal for all these values than those of patients in the other groups. Group 3 patients had symptoms an average of more than 2 weeks longer before diagnosis, and had significantly lower serum uric acid and higher calcium levels than patients in the other groups had. No differences were detected among the groups in age at diagnosis, gender, or survival rate. We conclude that children with acute lymphoblastic leukemia who have prominent bone pain preceding the diagnosis frequently have nearly normal hematologic values and that this feature may contribute to a delay in diagnosis.

Duration and morbidity of newly diagnosed idiopathic thrombocytopenic purpura in children: a prospective nordic study of an unselected cohort☆

OBJECTIVEnTo determine the duration of the risk period with platelet counts <20 x 10(9)/L and the frequency of bleeding episodes in unselected children with idiopathic thrombocytopenic purpura (ITP).nnnSTUDY DESIGNnWe established a registry for patients with newly diagnosed ITP in the five Nordic countries, enrolling children aged 0 to 14 years with platelet counts <30 x 10(9)/L. Treatment centers prospectively reported presenting features, management details, and disease-related events during the first six months after diagnosis.nnnRESULTSnAt presentation (n=501), more than half of the children had a platelet count <10 x 10(9)/L, but only 15 (3.0%) had a hemorrhage requiring blood transfusion. During follow-up of 409 patients, thrombocytopenia resolved uneventfully in 277. A risk period was present in 376 cases. Among 283 with self-limiting ITP, 26 were at risk >1 month and 25 had 30 events. Among 93 patients with chronic ITP, 73 were at risk >1 month and 44 had 111 events. Events occurred with an average frequency of 0.39 per month at risk. Life-threatening hemorrhages did not occur in the first six months after diagnosis.nnnCONCLUSIONnMost children with ITP are at risk for serious bleeding for less than one month. Continuing severe thrombocytopenia is associated with little morbidity, bleeding episodes being infrequent and very rarely serious.

High white blood cell count at diagnosis of childhood acute lymphoblastic leukaemia: biological background and prognostic impact. Results from the NOPHO ALL‐92 and ALL‐2000 studies

Prognostic impact of peripheral blood white blood cell count (WBC) at the diagnosis of childhood acute lymphoblastic leukaemia (ALL) was evaluated in a population‐based consecutive series of 2666 children aged 1–15 treated for ALL between 1992 and 2008 in the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden). Ten‐year event‐free (pEFS10y) survival and overall (pOS10y) survival were 0.75u2003±u20030.01 and 0.85u2003±u20030.01, respectively. Although treatment intensity was determined by WBC, non‐remission and relapsed patients still had significantly higher WBC than those in remission for B‐cell precursor (BCP) (median WBC: 24.8 vs. 14.0 vs. 8.3u2003×u2003109/L, Pu2003<u20030.001), but not for T‐lineage (T‐ALL) (median WBC: 127.8 vs. 113.0 vs. 86.8u2003×u2003109/L, Pu2003=u20030.22). pEFS was inversely related to WBC for BCP (Pu2003<u20030.001), but not for T‐ALL. WBC was not associated with risk of event for BCP or T‐ALL for patients with minimal residual disease at the end of induction (MRDd29) <10−3. In contrast, for MRDd29u2003≥u200310−3 and <5% leukaemic blasts in bone marrow at day 29, the pEFS5y for WBCu2003<u2003100.0 (Nu2003=u2003152) vs. ≥100.0 (Nu2003=u200319) was 0.76 vs. 0.50 (Pu2003=u20030.001). That was the case both for BCP (pEFS5y 0.76 vs. 0.58) and for T‐ALL (pEFS5y 0.71 vs. 0.38). Whether the inferior EFS for the subset of patients with high WBC and slow initial response to treatment reflects rare or overlooked cytogenetic aberrations as well as the factors that determine WBC levels at diagnosis awaits exploration.

High-resolution comparative genomic hybridisation yields a high detection rate of chromosomal aberrations in childhood acute lymphoblastic leukaemia

Abstract: Background: Cytogenetic aberrations are of prognostic significance in childhood acute lymphoblastic leukaemias and a high detection rate could improve the biological understanding and classification of these diseases.

Intensive chemotherapy without radiotherapy gives more than 85% event-free survival for non-Hodgkin lymphoma without central nervous involvement: a 6-year population-based study from the nordic society of pediatric hematology and oncology.

Background The prognosis in childhood non-Hodgkin lymphoma (NHL) has improved dramatically during recent decades. The authors report the results from a 6-year population-based study of clinical characteristics and treatment results of NHL from the five Nordic countries. Methods All children younger than 15 years of age at diagnosis with NHL diagnosed from 1995 to 2000 were stratified and treated according to immunophenotypic classification and stage of disease. Results A total of 230 patients were diagnosed with primary NHL, which gives an annual incidence of 0.9/100.000 children, with a median age of 8 years. Seven percent of the children were below 3 years of age at diagnosis. The male/female ratio was 2.3 and was unrelated to age. Patients with pre-B and T-cell NHL constituted 33%, B-cell NHL 53%, and anaplastic large cell lymphoma (ALCL) 14%. According to Murphy’s classification, 14% had stage 1, 17% stage 2, 50% stage 3, and 19% stage 4 disease, 12 of whom (28%) had central nervous involvement (CNS) at diagnosis. By January 1, 2003, four children had died during induction, three children died in remission (2, 6, and 26 months from diagnosis), and 24 children experienced a relapse. At 5 years, the probability of event-free survival (p-EFS) was 86 ± 2% for all children. The 5-year p-EFS values for stages 1 through 4 were 94%, 97%, 83%, and 79%, respectively. The 5-year p-EFS values were 91% for B-cell, 87% for pre-B, 81% for ALCL, and 79% for T-cell NHL. The 12 patients with CNS involvement at diagnosis had a significantly poorer outcome than stage 4 patients with CNS involvement (p-EFS = 50% vs. 90%, P < 0.01). The 218 patients without CNS disease at diagnosis had a 5-year p-EFS of 88%. Conclusions With modern intensive chemotherapy, more than 85% of NHL patients will achieve long-lasting first remission. In the future, preventing death during induction and remission and improving therapy for patients with CNS disease would have a major impact on the overall p-EFS.

Effect of age and body weight on toxicity and survival in pediatric acute myeloid leukemia: results from NOPHO-AML 2004

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 2–9 (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.

NT5C2 germline variants alter thiopurine metabolism and are associated with acquired NT5C2 relapse mutations in childhood acute lymphoblastic leukaemia

The antileukaemic drug 6-mercaptopurine is converted into thioguanine nucleotides (TGN) and incorporated into DNA (DNA-TG), the active end metabolite. In a series of genome-wide association studies, we analysed time-weighted means (wm) of erythrocyte concentrations of TGN (Ery-TGN) and DNA-TG in 1009 patients undergoing maintenance therapy for acute lymphoblastic leukaemia (ALL). In discovery analyses (454 patients), the propensity for DNA-TG incorporation (wmDNA-TG/wmEry-TGN ratio) was significantly associated with three intronic SNPs in NT5C2 (top hit: rs72846714; Pu2009=u20092.09u2009×u200910−10, minor allele frequency 15%). In validation analyses (555 patients), this association remained significant during both early and late maintenance therapy (Pu2009=u20098.4u2009×u200910−6 and 1.3u2009×u200910−3, respectively). The association was mostly driven by differences in wmEry-TGN, but in regression analyses adjusted for wmEry-TGN (Pu2009<u20090.0001), rs72846714-A genotype was also associated with a higher wmDNA-TG (Pu2009=u20090.029). Targeted sequencing of NT5C2 did not identify any missense variants associated with rs72846714 or wmEry-TGN/wmDNA-TG. rs72846714 was not associated with relapse risk, but in a separate cohort of 180 children with relapsed ALL, rs72846714-A genotype was associated with increased occurrence of relapse-specific NT5C2 gain-of-function mutations that reduce cytosol TGN levels (Pu2009=u20090.03). These observations highlight the impact of both germline and acquired mutations in drug metabolism and disease trajectory.

Methotrexate polyglutamate levels and co-distributions in childhood acute lymphoblastic leukemia maintenance therapy

PurposeMethotrexate polyglutamates (MTXpg) facilitate incorporation of thioguanine nucleotides into DNA (DNA-TG, the primary cytotoxic thiopurine metabolite and outcome determinant in MTX/6-mercaptopurine treatment of childhood ALL). We hypothesized that mapping erythrocyte levels of MTXpg with 1–6 glutamates and their associations with DNA-TG formation would facilitate future guidelines for maintenance therapy dosing.Methods and resultsSummed MTX with 1–6 glutamates resolved by LCMS [median (interquartile): 5.47 (3.58–7.69) nmol/mmol hemoglobin] was in agreement with total MTX by radio ligand assay. In 16,389 blood samples from 1426 ALL maintenance therapy patients, MTXpg3 21.0 (15.2–27.4)% was the predominant metabolite, and MTXpg1 (the maternal drug) constituted 38.6 (27.2–50.2)% of MTXpg1–6. All subsets correlated; the strongest associations were between metabolites with similar polyglutamate lengths. Correlations of MTXpg1 with MTXpg2 and MTXpg3,4,5,6 were rsu2009=u20090.68 and rsu2009=u20090.25–0.42, respectively. Intercorrelations of MTXpg3,4,5,6 were all rsu2009≥u20090.51. MTXpg4 accounted for 29.8 (24.7–33.3)% of MTXpg3–6, yet explained 96% of the summed MTXpg3–6 variation. MTXpg1–4, MTXpg1–6, MTXpg2–6 and MTXpg3 were all associated with DNA-TG levels (pu2009<u20090.00001), but collinearity precluded identification of the most informative subset.ConclusionsMeasuring erythrocyte MTXpg4 simplifies and can replace longer chain MTXpg monitoring. Resolving individual MTXpg identifies samples that are unsuitable for dose guidance due to high levels of MTXpg1 remaining in the plasma fraction because of recent MTX intake. All tested MTXpg subsets correlated with DNA-TG and may be used for ALL maintenance therapy dose adjustments, but the most informative subset remains to be identified.

Hyperleucocytosis in paediatric acute myeloid leukaemia – the challenge of white blood cell counts above 200 × 109/l. The NOPHO experience 1984–2014

Hyperleucocytosis in paediatric acute myeloid leukaemia (AML) is associated with increased morbidity and mortality. We studied hyperleucocytosis in 890 patients with AML aged 0–18 years 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 × 109/l and 57 (6%) had WBC ≥200 × 109/l. Patients with WBC ≥200 × 109/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 2 weeks (30% vs. 1% for all others), overall survival in this group was inferior to patients with WBC <200 × 109/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.