Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia

Abstract

Analysis of 2668 children with acute lymphoblastic leukemia (ALL) treated in two successive Nordic clinical trials (Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-92 and ALL-2000) showed that 75% of all patients are cured by first-line therapy, and 83% are long-term survivors. Improvements in systemic and intrathecal chemotherapy have reduced the use of central nervous system (CNS) irradiation to o10% of the patients and provided a 5-year risk of isolated CNS relapse of 2.6%. Improved risk stratification and chemotherapy have eliminated the previous independent prognostic significance of gender, CNS leukemia and translocation t(1;19)(q23;p13), whereas the post-induction level of minimal residual disease (MRD) has emerged as a new risk grouping feature. Infant leukemia, high leukocyte count, T-lineage immunophenotype, translocation t(4;11)(q21;q23) and hypodiploidy persist to be associated with lower cure rates. To reduce the overall toxicity of the treatment, including the risk of therapy-related second malignant neoplasms, the current NOPHO ALL-2008 protocol does not include CNS irradiation in first remission, the dose of 6-mercaptopurine is reduced for patients with low thiopurine methyltransferase activity, and the protocol restricts the use of hematopoietic stem cell transplantation in first remission to patients without morphological remission after induction therapy or with high levels of MRD after 3 months of therapy.

The frequency and prognostic impact of dic(9;20)(p13.2;q11.2) in childhood B-cell precursor acute lymphoblastic leukemia: results from the NOPHO ALL-2000 trial

“…Our study and several other reports 3,4,6,7 strongly indicate that a substantial proportion (16-25%) of the dic(9;20)-positive cases relapse and that there is marked risk for CNS relapse. In fact, in the present series, comprising of 29 dic(9;20)-positive cases strictly treated according to the NOPHO-ALL 2000 protocol, 17 pEFS at 5 years (0.69) was significantly lower than for the traditional standard risk genetic subgroups high hyperdiploidy and t(12;21) ( Table 2). Although a second remission often could be achieved, leading to a pOS of 0.85, there was still a significantly worse outcome compared with t(12;21)-positive cases ( Table 2).…”

“…The strategies for Ara-C treatments are largely similar in the three protocols. 17,22,24 Thus, one could speculate that these drugs, when given as in the BFM protocol, may contribute to the more favorable outcome seen in the BFM study. 6 If correct, it becomes even more important to identify all dic(9;20)-positive cases using an interphase FISH strategy in order to assign the patients to correct risk groups and proper treatment regimens.…”

“…Among these, 1033 (88%) were BCP ALL, of which 882 (85%) were treated according to the NOPHO ALL 2000 protocol, which is described in detail elsewhere. 17 In short, risk stratification divided patients into standard intensity (SR: WBCX10 Â 10 9 /l, 1-9.9 years, no high risk (HR) features), intermediate intensity (IR: WBC410 Â 10 9 /l, age410 years, no HR features), and three HR groups (intensive, very intensive and extra intensive). HR features were WBCX100 Â 10 9 /l, 11q23/MLL rearrangement, t(9;22)(q34;q11), t(1;19)(q23;p13) and hypodiploidy (o45 chromosomes).…”

“…The dic(9;20) was not a risk stratifying aberration in the NOPHO-ALL-2000 protocol. 17 Thus, the choice of treatment intensity for patients with dic(9;20)-positive ALL was made solely on the basis of age, WBC count, the presence of extra-medullary leukemia and morphologic response during induction therapy.…”

“…By applying this FISH approach on a large Nordic pediatric series of BCP ALLs diagnosed between 2001 and 2006, and treated according to the NOPHO-2000 protocol, 17 we here show that the dic(9;20) is present in close to 5% of all cases, a frequency at least twice as high than the one based on G-banding analysis alone, [1][2][3][4][5][6][7] and that it is associated with a worse outcome (5-year event-free survival (EFS) and overall survival (OS) of 0.69 and 0.85, respectively) than standard risk patients.…”