New Gene Findings in Infant Acute Lymphoblastic Leukemia

Zosia Chustecka

December 08, 2009

December 8, 2009 (New Orleans, Louisiana) — A study of infants with acute lymphoblastic leukemia (ALL) has shown that different gene translocation patterns are associated with different outcomes. This work could eventually lead to individualized treatment approaches.

Dr. Blaine Robinson

The study, the largest to date to report molecular characterization in infant ALL, was presented here at the American Society of Hematology 51st Annual Meeting, and highlighted at a press briefing.

ALL is the most common leukemia in infants younger than 1 year old, but it is still relatively rare, with a little more than 100 cases diagnosed each year, or 20 cases per million individuals, explained lead researcher Blaine Robinson, PhD, from the Children's Hospital of Philadelphia in Pennsylvania.

"Infant ALL is one of the most difficult pediatric cancers to treat and it is often fatal," he said. "It's very resistant to chemotherapy, and the outcome in infants less than a year old is very poor compared with [older] children. Typically, the survival in infants ranges from 20% to 40%, as opposed to children, where its more like 80%."

The outcome in infants less than a year old is very poor when compared to [older] children.

One factor that is associated with poor outcome in infants is MLL translocation, a molecular abnormality in which the MLL gene on chromosome 11 breaks and then becomes joined with one of a number of different partner genes on other chromosomes, Dr. Robinson explained.

The team used various molecular techniques to identify MLL translocations and specific partner genes. Statistical tests were used to determine how these gene fusions affected outcome, and how they related to classic prognostic factors, such as age and low white blood cell count.

A total of 221 infants were studied, and MLL gene status was identified in 210 infants (95%).

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Dr. Blaine Robinson

The results show that 74% of infants with ALL had an MLL translocation; the most common partner genes were AF4, ENL, and AF9. Both AF4 (located on chromosome 4) and ENL (located on chromosome 19) negatively affected patient survival, whereas AF9 (located on chromosome 9) was associated with better survival.

When the researchers took into account classic prognostic features, they found — not surprisingly, Dr. Robinson noted — that the less favorable fusion of MLL with AF4 was associated with a higher white count, and that the fusion of MLL with AF9 was associated with a lower white blood cell count.

There was also an interaction with age: infants who were younger than 90 days old at diagnosis had a far worse outcome if they had translocations that fused MLL with AF4 or ENL. Regardless of age, AF9 was a favorable prognostic factor.

These are newly described associations, and they illustrate how disease biology and the classic prognostic factors are integrally connected, Dr. Robinson explained.

"We are now looking to use more sophisticated techniques to examine these associations further," he said, "to see if we can determine whether different partner genes are more responsive to different types of therapy."

"This is a good example of how understanding these diseases at the genetic [level] can lead to individualized therapies to improve the overall outcome," said Richard Larson MD, professor of medicine at the University of Chicago in Illinois, who moderated the press briefing.

Dr. Robinson has disclosed no relevant financial relationships. Dr. Larson reports receiving research funding from Amgen, Bristol-Myers Squibb, Celgene, Chroma Therapeutics, Novartis, and Sanofi-Aventis; receiving consultancy fees from Antisoma, Caremark, Hana Bioscineces, Novartis, and Trubion; having equity ownership in GlaxoSmithKline and Merck; and receiving patent royalties from UptoDate Inc.

American Society of Hematology (ASH) 51st Annual Meeting: Abstract 907. Presented December 8, 2009.

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