New Subtype of Childhood Leukemia With Poor Prognosis

Zosia Chustecka

January 21, 2009

January 21, 2009 — Researchers have identified a unique biologic subtype of childhood acute T-lymphoblastic leukemia (T-ALL) that has a poor prognosis when treated with standard intensive chemotherapy, and they suggest that an alternative treatment strategy involving hematopoietic stem cell transplantation might be a better option for these children.

In fact, their institution has already modified its approach to front-line treatment for this subgroup of patients, say Dario Campana, MD, PhD, and colleagues from St. Jude Children's Research Hospital, in Memphis, Tennessee, working in collaboration with researchers from the Universities of Padua and Monza, in Italy. Their work was published online January 13, 2008 in the Lancet Oncology.

The newly identified subtype involves early T-cell precursors (ETPs). In the studies reported, this new ETP-ALL subtype was found in 30 of the 239 patients studied (12.6%). The researchers found that these patients do not respond as well as typical T-ALL patients to standard intensive chemotherapy, and that they have a much worse prognosis.

The finding has already had an impact on how they treat these patients. "T-ALL is normally treated with chemotherapy alone," Dr. Campana explained, adding that hematopoietic stem cell transplant is reserved for patients who relapse and for those who have a very poor early response to treatment.

However, because of the extremely poor prognosis with chemotherapy treatment, "all patients with ETP-ALL are now candidates for transplant at our institution as soon as they achieve complete remission (i.e., within the first 6 months or so of therapy)," Dr. Campana told Medscape Oncology.

When asked about advice for other physicians, Dr. Campana said: "We cannot make general recommendations," because the best treatment depends on the setting and experience of each center.

The researchers identified the new subtype using a set of genes that are differentially expressed in ETPs to develop a cell-marker-profile (i.e., the ETP immunophenotype). Dr. Campana said that other groups should find this identification to be "quite easy using the criteria outlined in the paper. Immunophenotypic diagnosis of leukemia by flow cytometry is a standard procedure at most cancer centers, and the markers that we used are commonly used by most labs."

First Report of New Subtype in T-ALL

There have been 2 other recent reports of new subtypes of ALL, but both of these involved B-ALL, in which the leukemic cells have features of B-cell progenitors. This latest report involves T-ALL, in which the leukemic cells have T-cell progenitors, Dr. Campana explained. "All 3 studies took advantage of methods for genome-wide gene-expression analysis that have become recently available," he added.

T-ALL accounts for about 15% of cases of ALL in children and about 25% of cases in adults, Dr. Campana told Medscape Oncology. To date, there have been no reliable prognostic factors for these patients, and so all patients with T-ALL are treated uniformly in the major study protocols. The standard treatment is intensive chemotherapy, which achieves a cure rate of about 80%. The drugs typically used are glucocorticoids (prednisone or dexamethasone), vincristine, asparaginase, daunorubicin, methotrexate, and 6-mercaptopurine, and they are given in various combinations for around 2 to 2.5 years, Dr. Campana said.

New Subtype Resistant to Standard Chemotherapy

ETP-ALL originates from very immature hematopoietic cells (the early thymic progenitors), which have a very distinctive immunophenotype and gene-expression profile, Dr. Campana explained. These immature cells are recent migrants from the bone marrow to the thymus, and they retain stem-cell like features, with the ability to differentiate into several different types of thymocytes. They are quite different fromthe usual lymphoid cells found in typical ALL patients, and the researchers speculate that this makes them rather resistant to lymphoid-directed therapy, such as glucocorticoids and asparaginase.

"In our study, we found that ETP-ALL subtypes are resistant to glucocorticoids," Dr. Campana said. "However, the molecular mechanisms underlying this resistance remain to be determined. It is also unclear whether they specifically resist other components of ALL therapy."

In the portion of the study conducted in the United States, the ETP-ALL subtype was identified in 17 of 139 patients (12.2%) who were involved in several clinical trials at St Jude's Hospital.

A review of their records showed that they had a worse response to standard treatment than the typical group, and had significantly more minimal residual disease after the first phase of remission-induction therapy.

This subgroup also had a significantly worse outcome, the researchers note. The 10-year overall survival was only 19% in the ETP-ALL subgroup, compared with 84% for the typical group, and 10-year event-free survival was 22%, compared with 69%, respectively (P < .0001 for both).

In addition, all of the 9 remission failures or relapses recorded in the ETP-ALL subgroup occurred in the bone marrow, whereas half of the relapses (11 of 22) in the typical T-ALL subgroup were confined to extramedullary sites.

Validation in a Different Cohort of Patients

To validate these findings, the researchers repeated the study in Italy, and investigated a cohort of 100 patients who were enrolled in the Associazone italiana Ematologia Oncologia Pediatrica ALL-2000 study. They found the ETP-ALL subtype in 13 of these patients (13%).

The Italian data also showed that this subgroup of patients had early development of drug resistance, and significantly higher minimal residual disease than the typical patients. The data also showed a worse outcome. In this case, the 2-year overall survival for ETP-ALL patients was 45%, compared with 90% for typical ALL, and the 2-year event-free survival was 22%, compared with 71%, respectively. In addition, the cumulative incidence of remission failure or hematologic relapse was much higher, the researchers note: at 2 years, it was 57% for ETP-ALL and 14% for typical ALL.

The long-term response to therapy is one of the worst in recognized high-risk forms of childhood ALL.

"We have identified a unique biological subtype of childhood leukemia — ETP-ALL — which is associated with a high risk of remission-induction failure or relapse in patients treated with contemporary protocols of intensive chemotherapy for ALL," the researchers conclude. "The long-term response to therapy is one of the worst in recognized high-risk forms of childhood ALL."

This work was supported by grants from the US National Cancer Institute, the Italian Ministry for University and Research, and several other research foundations. The researchers have disclosed no relevant financial relationships.

Lancet Oncol. Published online January 13, 2009. Abstract

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