Marit Hellebostad

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 0.75 ± 0.01 and 0.85 ± 0.01, 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. 8.3 × 109/L, P < 0.001), but not for T‐lineage (T‐ALL) (median WBC: 127.8 vs. 113.0 vs. 86.8 × 109/L, P = 0.22). pEFS was inversely related to WBC for BCP (P < 0.001), 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 MRDd29 ≥ 10−3 and <5% leukaemic blasts in bone marrow at day 29, the pEFS5y for WBC < 100.0 (N = 152) vs. ≥100.0 (N = 19) was 0.76 vs. 0.50 (P = 0.001). 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.

Cellular drug sensitivity in MLL-rearranged childhood acute leukaemia is correlated to partner genes and cell lineage

Rearrangements in the 11q23 region, the site of the mixed lineage leukaemia (MLL) gene, are found in both childhood acute myeloid (AML) and lymphoblastic (ALL) leukaemia. We studied the in vitro drug resistance by the fluorometric microculture cytotoxicity assay (FMCA) in 132 children with AML and 178 children with ALL (aged 0–17 years). In AML, children with t(9;11) (n = 10) were significantly more sensitive to cytarabine (P < 0·001) and doxorubicin (P = 0·005) than non‐11q23 rearranged patients (n = 108). Children with other 11q23 rearrangements (n = 14) differed less from non‐rearranged children. The ‘AML‐profile’ common to all three groups included relative resistance to glucocorticoids and vincristine. In ALL, children with 11q23 rearrangement (n = 22) were significantly more sensitive to cytarabine (P = 0·026) than children without 11q23 rearrangement (n = 156), also after stratification for white blood cell count. In conclusion, the findings indicate that the cellular drug resistance is correlated to both the cell lineage and the type of 11q23 rearrangement. High cellular sensitivity to cytarabine and doxorubicin might explain the excellent treatment results in children with AML and t(9;11). The present study supports the strategy of contemporary protocols to include high‐dose cytarabine in the treatment of 11q23‐positive patients both in AML and ALL.

Translocation t(1;19) is related to low cellular drug resistance in childhood acute lymphoblastic leukaemia.

Translocation t(1;19) is related to low cellular drug resistance in childhood acute lymphoblastic leukaemia

Relapsed childhood acute lymphoblastic leukemia in the Nordic countries: prognostic factors, treatment and outcome.

Relapse is the main reason for treatment failure in childhood acute lymphoblastic leukemia. Despite improvements in the up-front therapy, survival after relapse is still relatively poor, especially for high-risk relapses. The aims of this study were to assess outcomes following acute lymphoblastic leukemia relapse after common initial Nordic Society of Paediatric Haematology and Oncology protocol treatment; to validate currently used risk stratifications, and identify additional prognostic factors for overall survival. Altogether, 516 of 2735 patients (18.9%) relapsed between 1992 and 2011 and were included in the study. There were no statistically significant differences in outcome between the up-front protocols or between the relapse protocols used, but an improvement over time was observed. The 5-year overall survival for patients relapsing in the period 2002–2011 was 57.5±3.4%, but 44.7±3.2% (P<0.001) if relapse occurred in the period 1992–2001. Factors independently predicting mortality after relapse included short duration of first remission, bone marrow involvement, age ten years or over, unfavorable cytogenetics, and Down syndrome. T-cell immunophenotype was not an independent prognostic factor unless in combination with hyperleukocytosis at diagnosis. The outcome for early combined pre-B relapses was unexpectedly poor (5-year overall survival 38.0±10.6%), which supports the notion that these patients need further risk adjustment. Although survival outcomes have improved over time, the development of novel approaches is urgently needed to increase survival in relapsed childhood acute lymphoblastic leukemia.

The effect of central nervous system involvement and irradiation in childhood acute lymphoblastic leukemia: Lessons from the NOPHO ALL-92 and ALL-2000 protocols.

Central nervous system irradiation (CNS‐RT) has played a central role in the cure of acute lymphoblastic leukemia (ALL), but due to the risk of long‐term toxicity, it is now considered a less‐favorable method of CNS‐directed therapy.

Rare MLL-ELL fusion transcripts in childhood acute myeloid leukemia—association with young age and myeloid sarcomas?

BackgroundThe chromosomal translocation t(11;19)(q23;p13) with a breakpoint within subband 19p13.1 is found mainly in acute myeloid leukemia (AML) and results in the MLL-ELL fusion gene. Variations in the structure of MLL-ELL seem to influence the leukemogenic potency of the fusion in vivo and may lie behind differences in clinical features. The number of cases reported so far is very limited and the addition of more information about MLL-ELL variants is essential if the possible clinical significance of rare fusions is to be determined.Case presentationCytogenetic and molecular genetic analyses were done on the bone marrow cells of a 20-month-old boy with an unusual form of myelomonocytic AML with multiple myeloid sarcomas infiltrating bone and soft tissues. The G-banding analysis together with FISH yielded the karyotype 47,XY, +6,t(8;19;11)(q24;p13;q23). FISH analysis also demonstrated that MLL was split. RNA-sequencing showed that the translocation had generated an MLL-ELL chimera in which exon 9 of MLL (nt 4241 in sequence with accession number NM_005933.3) was fused to exon 6 of ELL (nt 817 in sequence with accession number NM_006532.3). RT-PCR together with Sanger sequencing verified the presence of the above-mentioned fusion transcript.ConclusionsBased on our findings and information on a few previously reported patients, we speculate that young age, myelomonoblastic AML, and the presence of extramedullary disease may be typical of children with rare MLL-ELL fusion transcripts.

Treatment-related mortality in relapsed childhood acute lymphoblastic leukemia

Treatment of relapsed childhood acute lymphoblastic leukemia (ALL) is particularly challenging due to the high treatment intensity needed to induce and sustain a second remission. To improve results, it is important to understand how treatment‐related toxicity impacts survival.