The 20% of children with T-lymphoblastic leukaemia (T-ALL) who fail to respond to standard intensive chemotherapy may have a newly identified subtype of the disease, concludes an Article published early Online and in the February edition of The Lancet Oncology.

The overall outcome of patients with T-ALL, which accounts for 10-15% of all childhood lymphoblastic leukaemias, has improved over the last few years. Intensive chemotherapy currently achieves cure rates of 80%. Further improvements in survival have been thwarted, however, because it has proved very difficult to identify reliable clinical features or cell markers that can accurately predict which patients are most likely to experience treatment failure with standard protocols.

Dario Campana and colleagues developed a theory that the cells involved in the group of non-responders could be immature, early T-cell precursors (ETPs), a subset of thymocytes that have only recently been identified and characterised. ETPs may be directly derived from haemopoietic stem cells in the bone marrow and retain the potential to differentiate into several types of thymocyte. They represent recent migrants from the bone marrow to the thymus and may resist treatment because they are substantially different to the lymphoid cells that standard chemotherapy is designed to eliminate.

In this study, Dr Campana and colleagues examined the leukaemic cells of 239 T-ALL patients from two study centres, one in the USA and one in Italy. Using gene-expression profiling, flow cytometry, and single nucleotide polymorphism array analysis, they identified 30 patients with leukaemic lymphoblasts that had the characteristics of ETPs, noting that the genomic instability of tumour cells in these patients was significantly increased.

When survival rates in ETP-ALL patients were compared with the survival rates observed in patients with typical T-ALL, the prognosis for the ETP-ALL profile was found to be very poor. In the US-based group, 72% of patients with ETP-ALL experienced remission failure or relapse within 10 years, compared with only 10% of typical T-ALL patients. Similar outcomes were noted in the Italian group, where 57% of ETP-ALL patients relapsed within 2 years, compared with 14% of typical T-ALL patients.

"The high risk of remission failure or subsequent relapse for patients with ETP-ALL, if treated with standard intensive chemotherapy, indicates the need for alternative approaches to treatment", stressed Dr Campana. He and his colleagues propose that an alternative treatment option for ETP-ALL could include myeloablative therapy, followed by haemopoietic stem-cell transplantation in first remission. Beyond that, further investigation of ETPs might also suggest treatment strategies that could repress the genetic programming making them more responsive to conventional lymphoid-cell-directed therapy.

"Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia."
Elaine Coustan-Smith MS, Charles G Mullighan MD, Mihaela Onciu MD, Prof Frederick G Behm MD, Prof Susana C Raimondi PhD, Deqing Pei MS, Cheng Cheng PhD, Xiaoping Su PhD, Jeffrey E Rubnitz MD, Prof Giuseppe Basso MD, Prof Andrea Biondi MD, Prof Ching-Hon Pui MD a b d, Prof James R Downing MD, Prof Dario Campana
The Lancet Oncology, Early Online Publication, 14 January 2009
Click here to read Summary online.

Notes

- 139 of the 239 patients with T-ALL were enrolled in Total Therapy Studies XIII, XIV, and XV at the St Jude Children's Research Hospital, Memphis, TN, USA. The remaining 100 patients were enrolled in the Italian national study Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) ALL-2000.

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Tony Kirby
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