Early Intensification of Intrathecal Chemotherapy Reduces Risk of Relapse in Pediatric ALL

Two additional doses of intrathecal therapy early during induction treatment for children with newly diagnosed acute lymphocytic leukemia (ALL) who were at increased risk for central nervous system (CNS) relapse improved disease control in the CNS, according to results from the St. Jude Total Therapy Study 16 published in the Journal of Clinical Oncology. However, higher doses of PEG-asparaginase, another therapy-intensification strategy evaluated in the trial, failed to improve patient outcomes compared with standard doses.

Although 5-year event-free survival (EFS) rates for pediatric ALL have reached more than 80% with contemporary treatment and overall survival (OS) exceeds 90%, study authors, led by Sima Jeha, MD, from St. Jude Children’s Research Hospital in Memphis, explained that a portion of patients experience CNS relapse, even with prophylactic intrathecal therapy, cranial irradiation, or both.

With Total Therapy Study 16, investigators sought to improve CNS disease control through 2 strategies:

  • administering a higher dose of PEG-asparaginase (3,500 U/m2, rather than 2,500 U/m2) to enhance asparagine depletion in the cerebrospinal fluid and blood to prevent CNS leukemia
  • intensifying intrathecal chemotherapy during early remission induction in patients who had features associated with increased CNS relapse

Of 598 patients (median age = 6 years; range = 0-19) enrolled between October 2007 and March 2017, 414 were eligible for the primary objective analysis and were randomly assigned to receive PEG-asparaginase 2,500 U/m2 (n=208) or 3,500 U/m2 (n=206). The 359 participants (60% of the study population) who presented with features associated with an increased risk of CNS relapse (including black race, any degree of CNS involvement at diagnosis, T-cell ALL, infant ALL, and TCF3-PBX1 fusion in the leukemia cells) were equally distributed between randomized arms.

All patients received induction therapy with prednisone, vincristine, daunorubicin, and PEG-asparaginase, followed by cyclophosphamide, cytarabine, and thiopurine, with protocol-defined dose modifications. Patients with Philadelphia chromosome–positive disease also received dasatinib 40 mg/m2 twice daily from day 22 until the end of treatment.

“Additional improvement in outcome will need to rely more heavily on molecular therapeutic and cellular immunotherapy approaches.”

—Sima Jeha, MD

For patients at increased risk for CNS relapse, 2 extra doses of intrathecal chemotherapy were administered during the first 2 weeks of induction. Prophylactic cranial irradiation was not performed.

Among all enrolled patients, the 5-year EFS rate was 88.2%, the overall survival (OS) rate was 94.1%, and the cumulative risk of isolated or combined CNS relapse was 1.5%. After adjustment for leukocyte count, minimal residual disease after induction, CNS status, and other factors, the only characteristic independently associated with CNS relapse was T-cell phenotype (hazard ratio = 5.15; 95% CI 1.3-20.6; p=0.021).

In the randomized analysis, higher doses of PEG-asparaginase did not appear to affect the likelihood of achieving continuous complete remission (primary endpoint): 90.4% with conventional dose versus 91.2% with higher dose (p=0.91). The risk of CNS relapse also was similar between the 2 arms (1.1% vs. 1.0%; p=0.55).

However, intensification of intrathecal chemotherapy was associated with a lower likelihood of CNS relapse, compared with historical controls, the authors reported. The 5-year cumulative risks of CNS relapse were as follows:

  • any CNS relapse: 1.8% in the intensive group vs. 5.7% in the standard group (p=0.008)
  • isolated CNS relapse: 1.5% vs. 4.0% (p=0.049)

“Remarkably, none of the patients in some of the higher-risk categories experienced CNS relapse, including 34 patients with a traumatic lumbar puncture with blasts, 15 with Philadelphia chromosome, [and] 12 with infant ALL,” Dr. Jeha and researchers noted.
There also were no significant differences in the cumulative risks of seizure (5.9% vs. 6.5%; p=0.78) or infection (8.1% vs. 8.4%; p=0.95) during induction between patients enrolled in Total Therapy Study 16 and historical controls with high-risk features.

In discussing their results, the authors noted that the improved CNS control observed in the study could also be attributable to higher doses of dasatinib and dexamethasone and not necessarily to the increased intrathecal therapy, potentially limiting the implications of these findings.

Dr. Jeha and co-authors also pointed to the lack of improvement in OS in this trial, compared with the earlier studies that evaluated a similar chemotherapy approach. “The intensity of conventional chemotherapy has reached its limit,” the researchers suggested. “Thus, additional improvement in outcome will need to rely more heavily on molecular therapeutic and cellular immunotherapy approaches.”

Study authors report relationships with Enzon Pharmaceuticals, which sponsored the study.

Reference

Jeha S, Pei D, Choi J, et al. Improved CNS control of childhood acute lymphoblastic leukemia without cranial irradiation: St Jude Total Therapy Study 16. J Clin Oncol. 2019;37:3377-91.