Pinpointing a high-risk leukaemia promises better treatment

For the first time, St. Jude researchers have identified a subtype of acute T-lymphoblastic leukaemia (T-ALL) that is resistant to standard chemotherapy. They are planning to use this new insight to diagnose the disease in children with the subtype and to use bone marrow transplants to more effectively treat the disease.

Even though treatment of T-ALL succeeds in about 80 percent of cases, about a fifth of children with the disease succumb to it. The researchers’ finding of the new subtype indicates that it will be possible to identify and treat more of these high-risk cases.

T-ALL is a cancer of white blood cells called T cells, in which the cells proliferate uncontrollably, crowding out normal cells and spreading to other organs. While chemotherapy can kill off cancerous T cells, the T-ALL subtype identified by Dario Campana, MD, PhD, Oncology and Pathology, and his colleagues arises from early T cell precursors (ETPs). These are newly made immature T cells that have turned cancerous and are resistant to chemotherapy targeted to T cells.

“Before our work, it had been known that there were different subtypes of T-ALL, with different cell markers and gene expression characteristics,” said Campana, the paper’s senior author. “But these classifications never gave us a strong enough prognostic indication to make a clinical decision on how to treat children with T-ALL.”

Campana and his colleagues described how they pinpointed cases of ETP-ALL in an article published online January 14 in the journal The Lancet Oncology.

They used genetic and immune screening to analyse the leukemic cells of 139 St. Jude patients, seeking the telltale signature of early T cell precursors. These analyses revealed 17 patients with just such a signature, indicating a distinct ALL subtype.

“When we looked at the treatment response of patients with this subtype that we identified, we found they had a very poor early treatment response, and overall they had a poor clinical outcome,” Campana said. “They all had residual leukemic cells detectable after two weeks of chemotherapy, compared to about half of typical cases. And the majority of these patients subsequently relapsed or never really achieved clinical remission.”

To validate their findings in a different population of patients, the researchers analysed 100 patients from the Italian national study Associazione Italiana Ematologia Oncologia Pediatrica. Those analyses revealed 13 patients with the ETP-ALL signature, who also showed the same poor treatment response.

“From these findings, for the first time we have identified a clear subset of patients with T-ALL who have a much higher risk of treatment failure than other patients,” Campana said. “Since these patients cannot be cured with conventional chemotherapy, we need new therapy strategies.”

St. Jude has already begun planning such an alternative treatment on patients with ETP-ALL, Campana said. This therapy—developed for patients with high-risk leukaemia’s—involves using irradiation and drugs to eradicate the patient’s bone marrow cells and transplanting new blood-forming stem cells.

Further studies could lead to other treatments for ETP-ALL, including drugs that would trigger ETPs to mature, rendering them sensitive to chemotherapy.

The researchers’ identification of ETP-ALL also suggests that there may be other chemotherapy-resistant ALLs whose identification could lead to better treatment for patients with poor prognosis.

“As we use new gene-analysis technologies to learn more about the molecular features of leukaemia, we should be able to identify other subsets of patients who respond poorly despite very intensive chemotherapy,” Campana said.

(Source: St. Jude Children’s Research Hospital: The Lancet Oncology: March 2009)