Improved CNS Control of Childhood Acute Lymphoblastic Leukemia Without Cranial Irradiation: St Jude Total Therapy Study 16

Abstract

PURPOSE Despite contemporary treatment, up to 10% of children with acute lymphoblastic leukemia still experience relapse. We evaluated whether a higher dosage of PEG-asparaginase and early intensification of triple intrathecal therapy would improve systemic and CNS control. PATIENTS AND METHODS Between 2007 and 2017, 598 consecutive patients age 0 to 18 years received risk-directed chemotherapy without prophylactic cranial irradiation in the St Jude Total Therapy Study 16. Patients were randomly assigned to receive PEG-asparaginase 3,500 U/m2 versus the conventional 2,500 U/m2. Patients presenting features that were associated with increased risk of CNS relapse received two extra doses of intrathecal therapy during the first 2 weeks of remission induction. RESULTS The 5-year event-free survival and overall survival rates for the 598 patients were 88.2% (95% CI, 84.9% to 91.5%) and 94.1% (95% CI, 91.7% to 96.5%), respectively. Cumulative risk of any—isolated or combined—CNS relapse was 1.5% (95% CI, 0.5% to 2.5%). Higher doses of PEG-asparaginase did not affect treatment outcome. T-cell phenotype was the only independent risk factor for any CNS relapse (hazard ratio, 5.15; 95% CI, 1.3 to 20.6; P = . 021). Among 359 patients with features that were associated with increased risk for CNS relapse, the 5-year rate of any CNS relapse was significantly lower than that among 248 patients with the same features treated in the previous Total Therapy Study 15 (1.8% [95% CI, 0.4% to 3.3%] v 5.7% [95% CI, 2.8% to 8.6%]; P = .008). There were no significant differences in the cumulative risk of seizure or infection during induction between patients who did or did not receive the two extra doses of intrathecal treatment. CONCLUSION Higher doses of PEG-asparaginase failed to improve outcome, but additional intrathecal therapy during early induction seemed to contribute to improved CNS control without excessive toxicity for high-risk patients.

Pediatric acute lymphoblastic leukemia

“…[1][2][3][4][5][6][7][8][9] However, OS for the St. Jude Total Therapy Study XVI (94.3%) was similar to that for the Total Therapy Study XV (93.5%) ( Figure 1). 9 Therefore, with the conventional approach, the chemotherapy intensity has been raised to the limit of tolerance, and further improvements in outcomes and reduction of adverse effects will require novel therapeutic approaches. Historically, genetic factors identified by conventional karyotyping have been used to diagnose ALL and to risk-stratify children with the disease.…”

“…The t(1;19)(q23;p13) translocation and variants encode TCF3-PBX1, 40 which is more common in African Americans and is associated with more frequent central nervous system (CNS) relapse and inferior outcomes with older, 41 but not contemporary, treatment regimens. 9 The t(9;22)(q34;q11.2) translocation results in the formation of the Philadelphia chromosome that encodes BCR-ABL1 and is found in a subset of childhood ALL that was also associated with unfavorable outcomes, although the prognosis has now been improved with combined chemotherapy and tyrosine kinase inhibition. 42 Rearrangement of KMT2A (MLL) at 11q23 to >80 partners, most commonly t(4;11)(q21;q23) encoding KMT2A-AFF1, is common in infant ALL and is associated with a dismal prognosis.…”

“…121 The St. Jude Total XVI study used intensified intrathecal therapy during induction therapy and obtained a remarkable reduction in 5-year cumulative isolated and combined CNS relapses to 1.3% and 1.5%, respectively, without cranial irradiation (Table 1). 9 In addition to CNS 3 at diagnosis, CNS 2 status (<5 WBC/mL and blasts) at diagnosis is associated with worse outcomes and greater risk of CNS relapse, and augmented intrathecal chemotherapy is required. 122 Traumatic lumbar puncture at diagnosis can introduce circulating ALL blasts into the cerebrospinal fluid (CSF) and is also associated with worse outcomes.…”

Asparaginase formulation impacts hypertriglyceridemia during therapy for acute lymphoblastic leukemia

“…6,17 Our aim was to compare triglycerides, risk factors for hypertriglyceridemia, and associated toxicities in two front-line pediatric ALL trials that used identical glucocorticoid regimens but different formulations of asparaginase: Total XV study (native L-asparaginase) and Total XVI study (PEG-asparaginase). [21][22][23] with SHR patients receiving more intensive treatment.…”

Prospective randomized trial of interventions for vincristine‐related neuropathic pain

“…However, gabapentin continues to be used for VCR‐related NP in various treatment regimens despite a lack of data from relevant pediatric clinical trials. We performed the current study to prospectively investigate gabapentin's value for treatment of VCR‐related NP in children with ALL treated on Total XVI protocol 12 …”