January 9, 2009 — Although improved therapies have dramatically increased cure rates in children with acute lymphoblastic leukemia (ALL), up to 20% of patients will still relapse after initial treatment. Survival among patients who experience relapse remains poor. However, new research suggests that alteration of IKZFI, a gene that encodes the protein IKAROS, is associated with a poor outcome in B-cell progenitor ALL. The findings were published online January 7 in the New England Journal of Medicine.
"We found a genetic abnormality that predicts a very high risk for relapse," said Charles Mullighan, MD, assistant member in the Department of Pathology at St. Jude Children's Research Hospital, in Memphis, Tennessee, and the paper's first author. "Using these genetic approaches, we are gaining new insight into the disease and developing new therapeutic approaches."
The study was conducted as part of the National Cancer Institute's Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, which seeks to use modern genomic technologies to identify therapeutic targets in childhood cancers. The researchers found that, in multivariate analysis, the association between IKZFI status and outcome was independent of confounders that included age, leukocyte count at presentation, cytogenetic subtype, and level of minimal residual disease.
Overall, 66.5% of the cohort with high-risk ALL had at least 1 mutation of genes regulating B lymphoid development, the authors note and, of this group, deletion of IKZFI was detected in 28.6% of patients. Deletion or mutation of IKZF1 was significantly associated with an increased risk for relapse, adverse events among low- and high-risk patients, and elevated levels of minimal residual disease.
"The key message is that this is a new predictor of poor outcomes and provides additional information over the existing testing panel," Dr. Mullighan said in an interview.
These findings, the authors note, indicate that detecting IKZFI alterations at the time of diagnosis might be useful in identifying patients who are at a high risk for treatment failure.
But there are no immediate plans to change therapy based on these findings, coauthor Gregory H. Reaman, MD, chair of the Children's Oncology Group, told Medscape Oncology. "These and similar observations are expected to drive the development of targeted agents, based on specific gene alterations, for children with ALL, with the goal to both improve outcome with such specific therapy and to minimize the risk of serious late effects of conventional therapy approaches."
Before making treatment decisions based on these findings early in the planned treatment, Dr. Reaman explained, a prospective evaluation of the impact of early treatment interventions is required. "At present, we have insufficient information to know whether existing therapy approaches will improve outcome," he said. "Further research is needed. It is expected that as this and other specific genetic alterations are defined, using this information to develop specific molecularly targeted therapy approaches is the required next step."
Dr. Mullighan agreed that their results need to be validated by other groups, and it is difficult to speculate at this time how these findings will affect therapeutic decisions. "We need to tailor the intensity of therapy appropriately, as we want it to cure the disease but not cause too much toxicity," he said.
Association with Increased Risk for Relapse
Genetic data were analyzed in a cohort of 221 children with high-risk B-cell progenitor ALL, using single-nucleotide polymorphism microarrays, transcriptional profiling, and resequencing of samples that were obtained at diagnosis. The patients had all been previously treated in the Children's Oncology Group P9906 study, and were enrolled from May 2000 to April 2003. The median follow-up time was 3.94 years (range, 0.16 to 6.20).
To confirm that specific genetic changes were associated with relapse, the researchers tested their hypothesis in an independent validation cohort of 258 patients with B-cell progenitor ALL. The children in the validation cohort were treated at St. Jude Children's Hospital, and the cohort included both standard- and high-risk patients.
In the primary cohort, the researchers identified a mean of 8.36 copy-number abnormalities per patient, with more than 50 recurring copy-number abnormalities in which the minimal common region of change involved 1 or a few genes. Of these, the most common deletions involved CDKN2A/B (45.7%), the lymphoid transcription-factor genes PAX5 (31.7%) and IKZF1 (28.6%), ETV6 (also known as TEL) (12.7%), RB1 (11.3%), and BTG1 (10.4%).
Among patients in both cohorts, deletion or mutation of IKZF1 was significantly associated with an increased risk for relapse and adverse events, and IKZF1 deletions were also associated with a poor outcome among patients in the validation cohort with BCR-ABL1-negative ALL.
The association was weaker for other genetic alterations, the authors observed. Deletions of EBF1 and BTLA/CD200 were associated with a poor outcome only among patients in the primary cohort, not among those in the validation group. An independent association between PAX5 lesions and outcome was also not observed in either cohort.
Increased Risk for Minimal Residual Disease
Elevated levels of minimal residual disease were strongly associated with an increased risk for relapse in both cohorts (at day 8 and day 29 in the original cohort, and at day 19 and day 46 in the validation cohort), which is consistent with previous data, the researchers note. In the original cohort, IKZF1 and EBF1 alterations were strongly associated with elevated levels of minimal residual disease, and high levels of residual disease were detected in patients with an IKZF1 deletion or mutation in the validation cohort.
No Test Available Yet
At present, there are no commercially available assays for detecting mutations in and overexpression of the IKZF1 gene. "This type of test may be somewhat complex, and several tests might be necessary," said Dr. Mullighan. "This might be beyond the reach of some hospital laboratories, and many would have to send the specimens out to a reference laboratory."
However, Dr. Reaman pointed out that in the setting of clinical trials within North America, such testing could be possible within the Children's Oncology Group Reference Laboratory mechanism. "It is likely that there are other genes that have similar predictive ability in identifying patients at increased risk of treatment failure, and ultimately the development of a commercially available laboratory test to make such evaluations generalizable for the entire global pediatric oncology community is a goal," he said. "In North America at the present time, testing would be possible for the overwhelming majority of children with ALL, since most patients are treated in [Children's Oncology Group] clinical trials."
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