Treatment for childhood acute lymphoblastic leukemia in Taiwan: Taiwan Pediatric Oncology Group ALL-2002 study emphasizing optimal reinduction therapy and central nervous system preventive therapy without cranial radiation

Background To eliminate cranial irradiation (CrRT)–related sequelae and to minimize the adverse impact of traumatic lumbar puncture (TLP) with blasts, the Taiwan Pediatric Oncology Group (TPOG) introduced a modified central nervous system (CNS)–directed regimen characterized by delayed triple intrathecal therapy (TIT) and the omission of CrRT for all children with newly diagnosed acute lymphoblastic leukemia (ALL). Methods This study compared the treatment outcomes of patients overall and patients with a non–CNS‐1 status (CNS‐2, CNS‐3, or TLP with blasts) in 2 treatment eras, one before and another after the revision of the TPOG‐ALL‐2002 protocol by the introduction of the modification (era 1 [2002‐2008] with CrRT and era 2 [2009‐2012] with delayed first TIT and no CrRT). Results There were no statistically significant differences in major outcomes between the 903 patients treated in era 1 and the 444 patients treated in era 2: the 5‐year event‐free survival (EFS) rates were 75.7% ± 1.4% and 72.1% ± 2.4%, respectively (P = .260), and the cumulative risks of isolated CNS relapse were 4.0% ± 0.7% and 4.1% ± 1.0%, respectively (P = .960). There were also no differences between non–CNS‐1 patients treated in era 1 (n = 76) and era 2 (n =28): the 5‐year EFS rates were 52.3% ± 5.8% and 62.9% ± 9.4%, respectively (P = .199), and the cumulative risks of isolated CNS relapse were 6.3% ± 3.1% and 3.6% ± 3.5%, respectively (P = .639). Notably, TLP with blasts was completely eliminated after the first TIT was delayed in era 2. Conclusions The delay of the first TIT until the clearance of circulating blasts and the total omission of CrRT did not compromise survival or CNS control in patients with childhood ALL, including those with a non–CNS‐1 status.

Section: Introductionsupporting

confidence: 60%

Section: Resultsmentioning

confidence: 52%

Section: Introductionmentioning

confidence: 64%

Section: Resultsmentioning

confidence: 99%

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Treatment of childhood acute lymphoblastic leukemia with delayed first intrathecal therapy and omission of prophylactic cranial irradiation: Results of the TPOG‐ALL‐2002 study

Yeh

Liang

Hou

et al. 2018

“…These results were not significantly different from those of the first 913 patients treated on the same protocol with prophylactic cranial irradiation before the revision. 19 Although delaying initial intrathecal therapy in this study reduced the risk of TLP+, there was concern that systemic chemotherapy given before diagnostic lumbar puncture might have eradicated or reduced leukemia cells in the cerebrospinal fluid and masked the diagnosis of CNS-2 or CNS-3 in patients who otherwise would have received intensified CNS-directed treatment, and the delay in intrathecal therapy might have also compromised the outcome of patients diagnosed to have a CNS-2 or CNS-3 status. To address these issues, Yeh et al 5 have updated their TPOG-ALL-2002 results in this issue of Cancer and limited them to the 903 and 444 patients with a known CNS status before and after the protocol revision, respectively.…”

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confidence: 78%

To delay or not to delay, that is the question for patients with acute lymphoblastic leukemia who do not receive prophylactic cranial irradiation

Pui

2018

Condensed abstract: To determine the impact of delaying diagnostic lumbar puncture and initial intrathecal therapy on treatment outcome of children with newly diagnosed acute lymphoblastic leukemia (ALL) treated without prophylactic cranial irradiation, Yeh and colleagues updated their TPOG-ALL-2002 clinical trial. They found that this treatment strategy reduced the rate of traumatic lumbar puncture with blasts to zero, and tended to improve outcome of patients with a CNS-2 or CNS-3 status based on the event-free survival, the overall survival, and the cumulative risk of CNS relapse, as compared to historical controls.

Clinical impact of minimal residual disease and genetic subtypes on the prognosis of childhood acute lymphoblastic leukemia

Jou

Su³

et al. 2022

Background This study analyzed data from two consecutive protocols for children newly diagnosed with acute lymphoblastic leukemia (ALL) to determine the clinical impact of minimal/measurable residual disease (MRD) and recently identified tumor genetic subtypes. Methods Genetic subtypes were determined by sequential approaches including DNA indexing, reverse transcriptase–polymerase chain reaction, multiplex ligation‐dependent probe amplification, and RNA‐sequencing. MRD was assessed by flow cytometry. The Taiwan Pediatric Oncology Group TPOG‐ALL‐2013 study enrolled patients who received MRD‐directed therapy. Results The 5‐year event‐free survival (EFS) and overall survival rates in the 2013 cohort were 77.8% and 86.9% compared to those of the 2002 cohort, which were 62.4% and 76.5%. Among patients treated with MRD‐guided therapy, those with ETV6‐RUNX1 fusion and high hyperdiploidy had the highest 5‐year EFS (91.4% and 89.6%, respectively). The addition of dasatinib improved outcomes in patients with BCR‐ABL1 ALL. Recently identified subtypes like DUX4‐rearranged, ZNF384‐rearranged, MEF2D‐rearranged, and PAX5alt subtypes were frequently positive for MRD after remission induction, and these patients consequently received intensified chemotherapy. Treatment intensification according to the MRD improved the outcomes of patients presenting DUX4 rearrangements. In high‐risk or very‐high‐risk subtypes, the TPOG‐ALL‐2013 regimen did not confer significant improvements compared to TPOG‐ALL‐2002, and the outcomes of BCR‐ABL1‐like, MEF2D‐rearranged, and KMT2A‐rearranged ALL subtypes (in addition to those of T‐cell ALL) were not sufficiently good. Novel agents or approaches are needed to improve the outcomes for these patients. Conclusions The TPOG‐ALL‐2013 study yielded outcomes superior to those of patients treated in the preceding TPOG‐ALL‐2002 study. This study provides important data to inform the design of future clinical trials in Taiwan. Plain language summary MRD‐directed therapy improved the outcomes for pediatric ALL, especially standard‐risk patients. Genomic analyses and MRD might be used together for risk‐directed therapy of childhood ALL. Our work provides important data to inform the design of future clinical trials in Taiwan