Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region

Summary

Background

The prognosis and optimum treatment of childhood acute lymphoblastic leukaemia (ALL) with abnormalities of chromosomal band 11q23 are controversial. We aimed to identify prognostic factors that might help in planning future therapy, and to assess the effectiveness of haemopoietic stem-cell transplantation in patients with the t(4;11) translocation, which is associated with a particularly poor outcome.

Methods

We reviewed data on 497 children and young adults who had ALL with various 11q23 abnormalities, including the translocations t(4;11), t(9;11), and t(11;19). All patients were treated with intensive chemotherapy, with or without haemopoietic stem-cell transplantation in first complete remission, by 11 study groups and single institutions from 1983 to 1995.

Findings

Age was the most important prognostic factor. In a Cox's proportional-hazard model stratified by 11q23 abnormalities, infants younger than 1 year fared significantly worse than patients 1 year of age or older (hazard ratio for event-free survival 1·84 [95% CI 1·38–2·47], p=0·0001). Among infants, any category of 11q23 abnormality conferred a dismal outcome, whereas in older patients, t(4;11) and t(9;11) were associated with a worse outcome than were other 11q23 changes. In the largest subgroup–256 patients with t(4;11)–any type of transplantation was associated with significantly worse disease-free survival (1·61 [1·10–2·35], p=0·014) and overall survival (1·76 [1·08–2·45], p=0·004) compared with chemotherapy only. Even transplantation with stem cells from HLA-matched related or HLA-matched unrelated donors tended to be associated with a worse outcome than chemotherapy alone.

Interpretation

The prognosis of acute lymphoblastic leukaemia with an 11q23 abnormality is particularly dismal in infants. Allogeneic transplantation with haemopoietic stem cells from an HLA-matched related donor does not seem to improve the clinical outcome in patients with t(4;11)-positive leukaemia.

Introduction

Chromosome band 11q23–the site of the mll (mixed-lineage-leukaemia) gene–is a region of recurrent rearrangements in the human acute leukaemias. Collectively, acquired abnormalities in the 11q23 region affect about 8% of children with acute lymphoblastic leukaemia (ALL).¹ MLL rearrangements are seen most often in patients with the common t(4;11)(q21;q23), t(11;19)(q23;p13·3), and t(9;11)(p21–22;q23) balanced translocations, are less frequent in patients with unbalanced or uncommon balanced translocations, and are rare in patients with deletion of the 11q23 region [del(11)(q23)].1, 2.

Several groups have called attention to the apparent clinical heterogeneity among patients with the t(11;19) or the t(4;11) rearrangements. Children 1–9 years old with the latter abnormality fared significantly better than older children and young adults, who in turn had a better outcome than infants and older adults.3, 4 Age also seemed of affect treatment outcome in two small series of B-lineage ALL patients with the t(11;19) translocation.5, 6 In one study, continuous complete remission was noted in five of seven children aged 1–9 years, but in only two of 13 infants and one of four children older than 10 years.⁵ In the report of the European Union Concerted Action Workshop on 11q23, seven of 10 infants, compared with five of 10 older children and adults, had an adverse event.⁶ A similar effect of age was seen in a recent Nordic series in which 26 of the 29 patients with 11q23 rearrangements had either the t(4;11) or the t(11;19) translocation.⁷

Because of their rarity, little is known about other 11q23 translocations or MLL rearrangements. Although most studies have related any 11q23 translocation or MLL rearrangement to a poor prognosis in infant ALL,8, 9, 10, 11, 12 two reports suggested that only the t(4;11) translocation conferred a dismal outcome in this age-group.13, 14 The prognostic significance of other 11q23 translocations or MLL rearrangements in older children with ALL is uncertain, although one study suggested that MLL rearrangements confer a poor prognosis irrespective of age.¹

The optimum treatment for patients with 11q23 translocations remains to be identified. The very poor outcome of treatment for patients with t(4;11)-positive ALL, especially those diagnosed during infancy, has led many oncologists to recommend allogeneic haemopoietic stem-cell transplantation. In two earlier reports on eight patients with 11q23 rearrangements who underwent this procedure, only one remained alive in remission at 33 months.15, 16 Two recent studies of patients with 11q23 translocations seem to show improved results for transplantation,17, 18 although in the study by Marco and colleagues,¹⁷ only two of the six survivors (median duration of continuous complete remission, 25 months) had the t(4;11) translocation. Pirich and colleagues¹⁸ reported long-term survival in four of seven patients undergoing transplantation, none of whom had the t(4;11) translocation. Hence, there are no compelling data to support the use of transplantation in infants with t(4;11) or, for that matter, in any subgroup of infants with any type of 11q23 translocation.

In this retrospective study of childhood ALL patients with 11q23 abnormalities, we sought to identify prognostic factors that would assist in planning future treatment and to assess the efficacy of haemopoietic stem-cell transplantation in patients with the t(4;11) translocation. We collected and centrally reviewed the data from 497 infants, children, and young adults with 11q23 abnormalities, who were treated by 11 participating cooperative groups and single institutions in the USA and Europe.