Dasatinib used during induction and consolidation in the Children’s Oncology Group (COG) AALL0622 trial provided early response rates for children with Ph-positive (Ph+) acute lymphoblastic leukemia (ALL), according to investigators.
But the early response rates did not improve event-free survival (EFS) compared to the use of consolidation imatinib in the AALL0031 study.
Incidence of cranial relapse was more than doubled in AALL0622 compared to AALL0031.
The investigators believe the incidence of cranial relapse may explain the results of AALL0622.
“We cannot yet conclude that the current dasatinib plus chemotherapy combination is better than imatinib plus chemotherapy,” the authors stated.
AALL0622 was designed to be an improvement on AALL0031, which demonstrated that adding the tyrosine kinase inhibitor (TKI) imatinib to intensive chemotherapy in the consolidation phase significantly improved survival for children with Ph+ ALL.
In AALL0622 dasatinib was given early in induction (day 15) and then in consolidation with the hope that patients could achieve early remission.
Another departure from AALL0031 was that cranial irradiation was not provided for control of central nervous system (CNS) metastasis. Because dasatinib accumulates in the CNS, which is a ‘sanctuary site’ for leukemia, it was presumed that patients could benefit from a TKI yet be spared from cranial irradiation.
As expected, adding dasatinib mid-induction provided a complete remission rate of 98% at the end of induction (day 29), which was better than the 89% seen in AALL0031.
In addition, more patients in AALL0622 showed minimal residual disease (MRD) <0.01% at the end of induction: 59% vs 25% in AALL0031 (P <0.001). At the end of consolidation, corresponding rates were 89% vs 71% for AALL0031.
For the primary outcome, 3-year EFS was 84.6% for patients in AALL0622 in standard-risk patients. Five-year OS and EFS rates were 86% and 60%, respectively.
In patients with overt brain metastasis (CNS3 status), 5-year CNS relapse was 15% for patients in the AALL0622 study vs 6.6% for patients in the AALL031 study.
However, 5-year OS rates were similar in the two groups of patients: 86% for AALL0622 vs 81% for AALL0031.
AALL0622 allowed the use of hematopoietic stem cell transplantation (HSCT) in high-risk patients as well as in standard-risk patients with a sibling donor.
Five-year OS and EFS for standard-risk patients (19% underwent HSCT at first remission) and high-risk patients (91% underwent HSCT in first remission) were similar.
Children who did not undergo HSCT had a similar 5-year OS of 88%, which suggested that children with Ph+ ALL should not undergo transplantation at first remission.
Samples from a subset of patients was analyzed for IKZF1 mutations and correlated with outcomes.
Five-year OS was 80% in those harboring the mutation versus 100% who had the wild-type gene (P=0.04); 4-year EFS was also significantly lower—10% vs 82% (P=0.04).
Screening for IKZF1 may be used to identify high-risk patients suitable for HSCT and/or alternate treatment, the authors note.
The investigators reported their findings in The Journal of Clinical Oncology.