domingo, 18 de diciembre de 2011

Genetic Profile in ALL -- Should All Patients Be Screened?

From Medscape Medical News > Oncology

Genetic Profile in ALL -- Should All Patients Be Screened?

Roxanne Nelson

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December 13, 2011 (San Diego, California) — New data support screening all patients newly diagnosed with acute lymphocytic leukemia (ALL) for the presence of high-risk subtypes. Identifying these patients will help characterize the genomic lesions driving a unique subtype of high-risk B-ALL, and help determine who will derive the most benefit from targeted therapies.
Dr. Kathryn Roberts

Relapsed ALL is a leading cause of cancer death in children, and multiple subtypes of the disease are characterized by specific genetic alterations, explained lead author Kathryn Roberts, PhD, from St. Jude Children's Research Hospital in Memphis, Tennessee, who presented the data here at the American Society of Hematology 53rd Annual Meeting.

"Researchers are finding that genetic determinants are important causes of treatment failure," Dr. Roberts said during a press briefing. "But it is currently not possible to increase the dose or intensity of current therapies because of toxicity."

Therefore, novel, less toxic, and targeted therapies are needed to improve survival in this population. Dr. Roberts noted that her group, along with other researchers, have identified a unique subtype of BCR-ABL-negative, high-risk B-ALL, with a deletion or mutation of IKZF1. This subtype has a gene-expression profile similar to BCR-ABL1-positive ALL.

"We refer to this new subtype as Ph-like ALL," she said. It is characterized by a gene-expression profile similar to Ph+ ALL, with IKZF1 alteration and poor outcome.

Up to 15% of pediatric ALL cases can be classified as Ph-like, she added. Previous clinical trials have shown that the outcome of these Ph-like ALL cases can be improved with the addition tyrosine kinase inhibitors, such as imatanib, to current chemotherapy regimens.

"This study represents potential changes in care," said Martin S. Tallman, MD, moderator of the press conference and chief of the leukemia service at the Memorial Sloan-Kettering Cancer Center in New York City. "This study provides further evidence that we can target specific leukemias with directed therapy, rather than just continue to give relatively indiscriminate chemotherapy. I think the whole field of small-molecule inhibitors is burgeoning."

Hunting for Genetic Alternations
The goal of the study, Dr. Roberts explained, was to identify novel genetic alterations in Ph-like ALL, which might also prove to be novel targets for directed therapies. To achieve this objective, a cooperative research study group was created, composed of the Children's Oncology Group, St. Jude Children's Research Hospital, the National Institutes of Health, and British Columbia Genome Sciences. Together, the team performed transcriptome sequencing (RNA-seq) on 12 cases of Ph-like B-ALL (10 from the P9906 Children's Oncology Group trial and 1 case each from St Jude Children's Research Hospital Total XV and XVI ALL trials), and whole-genome sequencing was done on 2 of these cases.

"Strikingly, we identified novel alterations in kinase or cytokine receptor signaling in 11 of the 12 cases studied," she said. These included novel rearrangements, structural variations, and sequence mutations dysregulating cytokine receptor and kinase signaling, she reported.

"The rearrangements included genes that have been reported to be dysregulated in other leukemias," Dr. Roberts said.

The authors validated putative rearrangements and sequence mutations using reverse transcription polymerase chain reaction (PCR), genomic PCR, and Sanger sequencing. The spectrum of alterations they observed included 3 cases with known IGH@CRLF2 rearrangement, 2 cases with the NUP214-ABL1 rearrangement, 1 case each with the in-frame fusions EBF1-PDGFRB, BCR-JAK2, and STRN3-JAK2, and 1 case with a cryptic IGH@-EPOR rearrangement.

A more detailed analysis of RNA-seq data revealed a 7.5 kb insertion of EPOR downstream of the enhancer domain in the IGH@ locus, which had not been detected with fluorescence in situ hybridization.
"We also screened a large number of these childhood cases to determine if any of these mutations were recurrent, and we did find similar lesions in other Ph-like ALL patients, suggesting that these lesions are a hallmark of this subtype of ALL," Dr. Roberts explained.

The authors then went on to determine if these lesions could be treated with currently available tyrosine kinase inhibitors such as imatanib. They found specifically that ABL1 and EBF1-PDGFRB rearrangements were sensitive to currently available tyrosine kinase inhibitors, including imatanib and dasatinib.

Dr. Roberts added that they went on to study the JAK2 arrangements, and that these fusions "responded remarkably well" to the JAK2 inhibitor ruxolitinib, which has recently received approval from the US Food and Drug Administration for the treatment of intermediate or high-risk myelofibrosis.

Complementary genomic approaches demonstrate that rearrangements, sequence mutations, and DNA copy number alterations dysregulating cytokine receptor and kinase signaling are a hallmark of Ph-like ALL, write the authors. Future directions in research include sequencing additional cases to determine the full spectrum of lesions, to reveal new targets, and to broaden the scope to include young adolescents and adults.

American Society of Hematology (ASH) 53rd Annual Meeting: Abstract 67. Presented December 12, 2011.
Genetic Profile in ALL -- Should All Patients Be Screened?

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