Mutational Analysis of BCR-Abl From Subjects with Relapsed Ph+ALL Treated On the COG Protocol AALL0031: a Report From the Children's Oncology Group.

Philadelphia chromosome positive Acute Lymphoblastic Leukemia (Ph+ALL) occurs in 2–5% of pediatric ALL and is associated with a poor prognosis. COG AALL0031 treated children with an intensified chemotherapy backbone plus imatinib. All subjects received imatinib at 340mg/m^2 daily. Exposure to imatinib progressively increased in each of five cohorts. Patients had a total imatinib exposure (before maintenance) of 42 days in cohort 1, 63 days in cohort 2, 84 days in cohort 3, 126 days in cohort 4, and 280 days in cohort 5. All groups received an additional 336 days of imatinib exposure in maintenance cycles 1 through 12 for approximately 2 years (with imatinb given on 21 day cycles for maintenance cycles 1 – 4, and a two-week on/two-week off schedule for maintenance cycles 5 - 12). Early results of this trial show encouraging outcome with a 3-year event free survival of 80±11% (95% CI 64 – 90%) for patients in cohort 5. In studies of adults with Ph+ALL treated with imatinib many patients recurred with imatinib resistant BCR-Abl mutations. To date, there are no data on the occurrence of BCR-Abl mutations in pediatric Ph+ALL.

We performed nested PCR to identify BCR-Abl point mutations in nine samples obtained at bone marrow (BM) relapse from Ph+ALL subjects on AALL0031.

(Table 1) Three samples from cohort 1 that had no exposure to imatinib prior to relapse showed wild-type sequence. There were 5 of 6 samples that also showed wild-type sequence. One sample was from cohort 2 and 3 samples were from cohort 3. Each subject relapsed 1 to 2 years after diagnosis while receiving varying amounts of imatinib with continued intensive therapy. One subject recurred after stem cell transplant in first remission. One sample from cohort 4 recurred after the completion of chemotherapy and imatinib. One subject from cohort 5 carried the histidine 396 to proline (H396P) mutation. This mutation, which increases the imatinib IC₅₀ by 10-fold, has been previously described to occur in adults with CML and Ph+ALL treated with imatinib. The subject from cohort 5 recurred 1 year after diagnosis on therapy with imatinib.

Only 1 resistant mutation in BCR-Abl has been identified among nine children with Ph+ALL treated on AALL0031. Therefore, unlike results in the adults, resistant mutations do not appear to drive early recurrence in Ph+ALL. Further studies will be needed to identify whether BCR-Abl mutations are identified in subjects who develop a late relapse after treatment with AALL0031 or subsequent treatment studies.

Druker:OHSU patent #843 - Mutate ABL Kinase Domains: Patents & Royalties; MolecularMD: Equity Ownership; Roche: Consultancy; Cylene Pharmaceuticals: Consultancy; Calistoga Pharmaceuticals: Consultancy; Avalon Pharmaceuticals: Consultancy; Ambit Biosciences: Consultancy; Millipore via Dana-Farber Cancer Institute: Patents & Royalties; Novartis, ARIAD, Bristol-Myers Squibb: Research Funding. Schultz:novartis: Membership on an entity's Board of Directors or advisory committees.