Postinduction Treatment for Specific ALL Subgroups
Infants with MLL gene translocations are generally treated on intensified chemotherapy regimens using agents not typically incorporated into frontline therapy for older children with ALL. However, despite these intensified approaches, EFS rates remain poor for these patients. The international Interfant clinical trials consortium utilized a cytarabine-intensive chemotherapy regimen, with increased exposure to both low- and high-dose cytarabine during the first few months of therapy, resulting in a 5-year EFS of 37% for infants with MLL translocations. The COG tested intensification of therapy with a regimen including multiple doses of high-dose methotrexate, cyclophosphamide, and etoposide, with a 5-year EFS of 34%.
The role of allogeneic stem cell transplant during first remission in infants with MLL gene translocations remains controversial. Case series have suggested that allogeneic transplants in first remission may be effective.[18,19,20]; [Level of evidence: 3iA] In a COG report that included 189 infants treated on CCG or POG infant ALL protocols between 1996 and 2000, there was no difference in EFS between patients who received stem cell transplant (SCT) in first complete remission (CR) and those who received chemotherapy alone. The Interfant clinical trials group, after adjusting for waiting time to transplantation, also did not observe any difference in disease-free survival (DFS) in high-risk infants (defined by prednisone response) with MLL translocations treated on the Interfant-99 trial with either allogeneic SCT in first CR or chemotherapy alone. However, in a subset analysis from the same trial, allogeneic SCT in first remission was associated with a significantly better DFS for infants with MLL translocations who were younger than 6 months at diagnosis and had either a poor response to steroids at day 8 or leukocytes ?300 g/L. In this subset, SCT in first remission was associated with a 64% reduction in the risk of failure resulting from relapse or death compared with chemotherapy alone.
The optimal treatment for infants without MLL translocations also remains unclear. On the Interfant-99 trial, such patients achieved a relatively favorable outcome with the cytarabine-intensive treatment regimen (4-year EFS was 74%). A favorable outcome for this subset of patients was obtained in a Japanese study using therapy comparable to that used to treat older children with ALL; however, that study was limited by small numbers.
Treatment options under clinical evaluation
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
- Interfant-06 Study Group trial: The Interfant-06 Study Group is conducting an international collaborative randomized trial (including sites in the United States) to test whether an ALL/acute myeloid leukemia hybrid regimen might improve outcomes for infants with MLL-rearranged ALL. The role of allogeneic transplantation in first remission is also being assessed in high-risk patients (defined as infants with MLL-rearranged ALL, younger than 6 months, and WBC >300,000 /�L) or poor peripheral blood response to steroid prophase. Infants with MLL-rearranged ALL with high MRD at end of consolidation phase are also eligible for allogeneic SCT in first remission regardless of other presenting features).
- COG-AALL0631: In this COG study of infant ALL, an FLT3 inhibitor, lestaurtinib, is being studied in infants with MLL rearrangement. Infants with MLL rearrangement are known to have a high level of FLT3 mRNA expression and lestaurtinib has been shown to selectively kill MLL-rearranged ALL cells in vitro and in vivo. This study combines lestaurtinib with intensive chemotherapy previously utilized in POG-P9407. There is an initial safety/activity phase followed by an efficacy phase in which children will be randomly assigned to chemotherapy with or without lestaurtinib. Infants with germline MLL will be nonrandomly assigned to less-intensive chemotherapy without lestaurtinib.