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Keywords: acute promyelocytic leukaemia, synthetic all-trans

retinoic acid, Tamibarotene, ATO, molecular remission.

First published online 5 July 2010

doi:10.1111/j.1365-2141.2010.08308.x

A Doctor(s) dilemma: ETV6-ABL1 positive acute lymphoblasticleukaemia

Leukaemic cells with the t(9;12)(q34;p13) produce a chimaeric

transcript resulting from the fusion of ETV6 at 12p13 with

ABL1 at 9q34. First described in 1995 (Papadopoulos et al,

1995) in a child with B-cell precursor acute lymphoblastic

leukaemia (ALL), ETV6-ABL1 positive leukaemias (acute and

chronic) are rare, with fully reported karyotypes in only nine

cases in the literature (Brunel et al, 1996; Golub et al, 1996;

Andreasson et al, 1997; Van Limbergen et al, 2001; La Starza

et al, 2002; Lin et al, 2002). Alternative splicing of ETV6 exons

is a common feature of these leukaemias (Bohlander, 2005).

Analogous to BCR-ABL1, the ETV6-ABL1 fusion protein has

elevated tyrosine kinase activity and therefore tyrosine kinase

inhibition with Imatinib might prove highly effective in the

treatment of ETV6-ABL1 positive ALL, as has been demon-

strated in ETV6-ABL1 positive chronic myeloid leukaemia

(Kawamata et al, 2008).

An 8-year old girl was hospitalized with a short history of

fever and back pain in association with lymphadenopathy and

hepatosplenomegaly. Her white cell count (WCC) was

282 · 109/l, Hb 118 g/l and platelet count was 40 · 109/l;

immunophenotyping of peripheral blood blasts confirmed

B-cell precursor ALL. On the basis of her presenting WCC

(>50 · 109/l) she was initially risk stratified as intermediate

risk and commenced a four drug (Dexamethasone, Vincristine,

Daunorubicin and Asparaginase) induction chemotherapy

according to the prospective multicentre trial UK ALL 2003.

Bone marrow cytomorphological analysis 8 d into treatment

showed 90% lymphoblasts. In the interim, fluorescence in situ

hybridization analysis showed a t(9;12)(q34;p13)/ETV6-ABL1

fusion and reverse transcription polymerase chain reaction

(RT-PCR) revealed expression of both ETV6 exon 4-ABL1 and

ETV6 exon 5-ABL1 transcripts (La Starza et al, 2002). She was

switched to the more intensive Schedule C, UK ALL 2003 and

Imatinib at a dose of 300 mg/m2 daily was immediately added

to her induction block of chemotherapy. By day 15 her bone

marrow blast count was less than 5% and minimal residual

disease (MRD) status at day 29, as assessed by allele-specific

oligonucleotide-PCR (IgH) was low risk (MRD negative or

positive <5 · 10)5). Ten months following diagnosis she

remains on continuous Imatinib therapy and in molecular

remission.

There are a number of important issues regarding this

particular patient’s optimal treatment that warrant further

discussion. First, should haematopoietic stem cell transplanta-

tion (HSCT) with a human leucocyte antigen (HLA) identical

related or unrelated donor be the treatment of choice in first

complete molecular remission? While the ETV6-ABL1 fusion

probably confers a poor prognosis similar to BCR-ABL1,

opinion is still divided as to the role of HSCT as standard

therapy in children and young adolescents with Ph+ ALL.

Recent data from the Children’s Oncology Group demon-

strated that the addition of imatinib to chemotherapy in this

cohort of Ph+ ALL is tolerable and confers a significant survival

advantage, albeit in historical controls (Schultz et al, 2009). The

authors went on to suggest that intensive poly-chemotherapy

plus Imatinib is, in fact, superior in terms of event-free survival

compared to HLA-matched HSCT from a related or unrelated

donor (Schultz et al, 2009). In this case, a 4/6 matched

Correspondence

ª 2010 Blackwell Publishing Ltd, British Journal of Haematology, 151, 84–109 101

unrelated umbilical cord was the only stem cell source available

so the decision to treat with Imatinib and high risk ALL

intensive poly-chemotherapy was taken.

Second, what is the true prognostic significance of low risk

MRD at day 29 in the context of the initial slow early response

at day eight (>90% blasts) and the rapid clearance of blasts by

day 15 (<5% blasts) following the addition of 7 d of Imatinib

therapy? Also, would low risk MRD status have been achieved

without the addition of Imatinib? Clearly these questions are

extremely difficult to answer and maybe not that clinically

relevant, as MRD status at the end of induction therapy is

probably the single most important determinant of outcome in

childhood and adolescent ALL, no matter how this is achieved,

although it should be stated that the significance of low risk

MRD following induction with this particular cytogenetic

abnormality remains unknown.

The third issue surrounds the optimum duration of tyrosine

kinase inhibition and for how long should molecular moni-

toring for MRD proceed? As there is no data in relation to

ETV6-ABL1 ALL, our approach is to continue Imatinib for

2 years following cessation of poly-chemotherapy as is done

with ATRA in acute promyelocytic leukaemia and Imatinib in

adult Ph+ ALL protocols. During this period of ‘Imatinib

maintenance’ molecular monitoring for MRD (paired bone

marrow and blood samples using RT-PCR for both ETV6 exon

4-ABL1 and ETV6 exon 5-ABL1 transcripts) would be carried

out every 3 months to predict impending relapse with a view

to pre-emptive therapy with a second generation tyrosine

kinase inhibitor with re-induction chemotherapy and revisit

the possibility of HSCT should this arise.

This case adds to the very sparsely reported clinical cases of

ETV6-ABL1 leukaemia in the literature and highlights the

difficulties faced in optimally treating these patients. Whilst

tyrosine kinase inhibition will most likely improve the

outcome, the optimal duration of treatment awaits clarifica-

tion. In the pre-Imatinib era HSCT clearly offered a survival

benefit over intensive chemotherapy alone, however, the

current role of transplantation in these rare leukaemias

remains to be ascertained.

Andrea Malone1

Stephen Langabeer2

Aengus O’Marcaigh1,3

Lorna Storey1

Christopher L. Bacon1

Owen P. Smith1,3

1Department of Haematology & Oncology, Our Lady’s Children’s

Hospital, 2Cancer Molecular Diagnostics, St James’s Hospital, and3Trinity College, Dublin, Ireland.

E-mail: owen.smith@tcd.ie

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Keywords: ETV6-ABL1, acute lymphoblastic leukaemia,

imatinib, haematopoietic stem cell transplantation.

First published online 6 July 2010

doi:10.1111/j.1365-2141.2010.08323.x

Correspondence

102 ª 2010 Blackwell Publishing Ltd, British Journal of Haematology, 151, 84–109