Analysis of immunoglobulin gene rearrangement for minimal residual disease as a prognostic parameter is a well established test in a variety of leukaemias such as ALL and CLL. The aim of this study was: 1) to analyse VH gene usage, occurrence of in-frame (IF) and out-of-frame (OF) sequences and rate of mutation; 2) to correlate these parameters with overall clinical outcome in adult ALL patients, as this may identify a novel prognostic marker in ALL, especially in the absence of other prognostic indicators.

Patients and methods: DNA from 82 de novo adult ALL patients (31F/51M) was obtained from PB or BM diagnostic samples. Using primers for the FR1 and JH segments, 102 clonal rearrangements were identified. Median WBC was 13.5 × 109/I (range 1.1–550 × 109/I). Sixty-three patients are, to date, in complete clinical remission (median follow up: 7 months; range: 3 weeks–82.5 months), 15 patients have relapsed (median relapse 5.7 mo; range: 2.1–22 mo) and 2 patients had resistant disease. Patients carrying the t(9;22) translocation and patients who received an allogeneic stem cell transplantation were excluded when calculating relapse free survival to avoid bias towards bad and good performance, respectively.

Results: A heterogeneous representation of VH gene usage was demonstrated. Recurrent rearrangements showed preferential use of VH3-66 (4 cases), VH1-2 (7 cases) and VH6 (8 cases; predominant in MLL-AF4 cases), when compared to the non-leukaemic controls (

Mortuza et al, 2002; JCO, 20:1094
). JH4 and JH6 were found in approximately equal proportions both in control and leukaemic groups, while JH5 (32 cases) was favoured in the leukaemic group. A similar trend was observed with D2-2 (23 cases) when compared to the other D segments in the latter.

There was a predominance of OF sequences (66 alleles; 64%; from 53 patients), although no statistical difference in relapse free survival between IF and OF was observed.

Mutations >1% were observed in 18/82 (22%) patients (18/102 alleles; 18%). These were twice as common in the IF sequences (11/18 patients; 61%) compared to OF sequences (in 6/17 pts, 35.3%). However mutations had no impact on overall survival (p=NS) and neither did immunophenotype (pre B Vs common ALL) (p=NS).

Conclusion: Unique to ALL patients, a considerable proportion of cases carry out-of-frame immunoglobulin rearrangements while a smaller proportion are in-frame, without any apparent clinical impact. In contrast to observations made in other leukemias, such as CLL, occurrence of mutation does not appear to affect clinical outcome in our data set, although a longer follow-up period may be required for this prognostic factor to be fully evaluated.

Topics:
acute lymphocytic leukemia, allogeneic stem cell transplant, brachial plexus neuritis, disease remission, dna, follow-up, genes, immunoglobulins, immunophenotyping, leukemia

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2005, The American Society of Hematology
2005
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