Triple Intrathecal Therapy Alone Was Delayed until the Disappearance of Blasts From Peripheral Blood in Children with Acute Lymphoblastic Leukemia: The Experience of a Single Hospital in Taiwan

The introduction of CNS-directed therapy had successfully improved the outcome of children with acute lymphoblastic leukemia (ALL). Pui et al. (N Engl J Med, 2009) demonstrated that with effective risk-adjusted systemic chemotherapy and intrathecal therapy initiated at diagnosis (Dx), cranial irradiation can be safely omitted from CNS-directed treatment in all children with newly diagnosed ALL. Manabe et al. (J Clin Oncol, 2001) reported a delay of diagnostic lumbar puncture (LP) and triple intrathecal therapy (TIT) after 1 week of prednisolone monotherapy. Starting 1999, in order to eliminate the adverse prognostic impact of traumatic LP with blasts, we conducted a prospective study of delayed TIT after the disappearance of blasts from peripheral blood (PB) on around 10 days of multi-drug induction therapy.

Since June 1999, children with ALL were treated with TIT alone without cranial irradiation, and chemotherapy with TPOG-ALL-93 or TPOG-ALL-2002 (activated in January 2002) protocols. These protocols had been reported previously (Leukemia, 2010). B-precursor ALL patients were stratified into standard risk (SR), high risk (HR) and very high risk (VHR) groups, according to age, WBC count, cytogenetics and molecular analysis at Dx. T-cell ALL was designated as VHR. The first TIT was performed until the disappearance of blasts from PB. If patients with persistent PB blasts on the treatment day 10 (D10), the TIT was planned. Furthermore, SR patient with detectable blasts on D10, the treatment was upgraded to HR group. Cranial irradiation was totally omitted in all patients. For patients with CNS-1 status, SR group received TIT 20 times in TPOG-ALL-93 and 14 times in TPOG-ALL-2002 protocols, respectively. HR patients with CNS-1 status received 23 and 17 times of TIT in TPOG-ALL-93 and 2002 protocols, respectively. In VHR group, TIT was administered 19 times for CNS-1. Additional TIT doses were given if patients with CNS-2 or CNS-3.

From June 1999 to August 2010, a total of 158 ALL patients were consecutively diagnosed at our hospital. There were 86 patients in SR group, 41 in HR and 31 in VHR, respectively. Six patients were excluded: 2 refusals to further treatment and 4 protocol violations. There were 86 boys and 66 girls enrolled. The median age at Dx was 4.1 years (range, 0.3–17.7 years) with 7 infants. The median WBC count at Dx was 12,100/μL (range, 800–596,000/μL). Fourteen had counts >100,000/μL. There were 141 patients of B-precursor ALL and 11 of T-cell ALL. At Dx, 17 patients (16 in SR and 1 in VHR) did not have detectable blasts on PB. In the remaining 135 patients, the blasts of 101 patients (74.8%) can be eliminated from PB after 10-day induction therapy, those included 77.9% of SR, 75.6% of HR and 65.4% of VHR, respectively. Six patients of SR group were upgraded to HR protocol since the detection of PB blasts on D10. Bleeding into the CSF at the time of LP was apparent in 4 patients (2.6%), but no leukemic blasts were identified in any patients.

As of July 31, 2012, the follow-up duration of 133 surviving patients ranged from 24 to 153 months (median, 88 months). The 7-year event-free survival and overall survival rates were 83.0 ± 3.2% (± SE) and 86.5 ± 3.1%, respectively. No isolated CNS relapse occurred. One infant with MLL rearrangement experienced combined CNS, BM and testicular relapses and one child with t(12;21) had combined CNS and molecular BM relapses. The cumulative risk of any CNS relapse was 1.5 ± 1.0% at 7 years.

A delay of TIT after disappearance of PB blasts with multi-drug induction therapy can effectively prevent CNS disease in children with ALL. Cranial irradiation can be completely omitted for CNS prophylaxis in our treatment protocols.

No relevant conflicts of interest to declare.