Between December 1991 and January 2008, 874 patients with ALL were enrolled onto four successive clinical trials (Total Therapy studies XIIIA,(12
) XIV (14
) and XV) at St. Jude Children’s Research Hospital. The treatment protocols were approved by the institutional review board at St. Jude, and Total XV was registered at ClincalTrials.gov, number NCT00137111. Signed informed consent was obtained from the patient’s parents or guardian with assent from the patients, as appropriate. Immunophenotype, cytogenetic and molecular genetic analyses were performed using standard methods, as described previously.(5
) Treatment plans have been described in details previously.(12
) In study XIIIA, all patients received triple intrathecal therapy on day 1, 22, and at the end of remission induction. Patients with CNS-2, CNS-3, or traumatic lumbar puncture with blasts received additional intrathecal treatments on days 8 and 15 of induction, and every 4 weeks during the first year of continuation therapy. Intensified intrathecal therapy was also administered to patients with high risk features (T-cell ALL with leukocyte count of at least 50×109
/L, B-cell precursor ALL with leukocyte count of at least 100 × 109
/L, or the presence of t(9;22)[BCR-ABL1
]), regardless of CNS status. Cranial irradiation plus 5 intrathecal treatments was given to patients who had CNS-3 status (24 Gy) or high-risk leukemia (18 Gy). The number of intrathecal therapy was 13 for lower-risk cases and ranged from 21 to 26 for higher-risk cases. In study XIIIB, we intensified systemic therapy by substituting dexamethasone for prednisone in post remission therapy. CNS-directed therapy was similar to that in study XIIIA except that cranial irradiation was limited to patients who had CNS-3 status (24 Gy), or with T-cell ALL and initial leukocyte count of 100 × 109
/L or greater (18 Gy). The total number of intrathecal treatments ranged from 13 in lower-risk cases to 26 in high-risk cases who received cranial irradiation. In study XIV, post-remission therapy was similar to that in Total XIIIB with some modifications including the use of higher dose methotrexate (5 g/m2
for higher-risk cases and 2.5 g/m2
for lower-risk cases), and dexamethasone. The total number of triple intrathecal treatments ranged from 16 in lower-risk cases to 23 in higher-risk cases with CNS-2, CNS-3 or traumatic lumbar puncture with blasts status at diagnosis. None of the patients received prophylactic cranial irradiation, regardless of CNS status or other features at diagnosis.
In study XV we revised the system of risk-assessment in which patients were assigned to low-, standard- and high-risk groups, based on sequential measurements of minimal residual disease. All patients received intrathecal therapy on day 1, 19 and at the end of remission induction. On days 8 and 26, additional intrathecal treatments were given to patients with high-risk features of CNS relapse (CNS-2, CNS-3, traumatic lumbar puncture with blasts, T-cell ALL with leukocyte count > 50×109/L, B-cell precursor ALL with leukocyte count > 100 × 109/L, or the presence of t(9;22)[BCR-ABL1], MLL rearrangement, or hypodiploidy < 45 chromosomes). Triple intrathecal chemotherapy was given every 8 weeks in low-risk cases and every 4 weeks in standard-or high-risk cases up to one year. Patients at high risk of CNS relapse continued to receive intrathecal therapy every 8 weeks until week 96 of continuation therapy. Depending on their CNS status, low-risk patients received 13 to 18, and standard-and high-risk cases 16 to 25, intrathecal treatments. No patient received prophylactic cranial irradiation.
We compared the outcome between 41 patients with pre-B ALL and the t (1
and 694 patients with other B-cell precursor ALL. The TCF3-PBX1
fusion was confirmed with RT-PCR and FISH in all 33 cases tested. Molecular testings were not performed in the first 8 cases because the probes were not available at that time. Because all cases with the (1
) have B-cell precursor phenotype, analysis was limited to patients with this immunophenotype and the 139 patients with T-cell ALL were excluded from the analyses. The median follow up time was 6.9 years (range 0.22 to 16.0 years). Overall survival and event-free survival (EFS) were estimated by the Kaplan-Meier method and compared with the Mantel-Haenszel (log-rank) test. The cumulative incidence of relapse was estimated by the method of Kalfleisch and Prentice and the functions were compared using the Gray’s test to adjust for competing events. The duration of EFS was defined as the time from diagnosis until the date of treatment failure (induction failure, relapse, death, or the development of a second malignancy) or until the date of last contact. Patients who did not attain a complete remission were considered failures to respond to therapy at time zero. The length of time at risk for relapse was computed from the date of achieving a complete remission to the date of relapse or the date of last contact, whichever came first. Death from non-relapse cause and second malignancy were included in the analysis and treated as competing events. The Cox proportional hazards model was used to identify independent prognostic factors.