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A Phase II Study of Chemotherapy Combined with Tyrosine Kinase Inhibitors for Children with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (JPLSG-ALL-Ph13)

JPLSG-ALL-Ph13 (JPLSG-ALL-Ph13)

43

Of 41 evaluable patients, 24 (58.5%) were male, the median age at diagnosis was 8.0(2.0-17.0), and no patient showed overt central nervous system leukemia at diagnosis. 6 patients (14.6%) had the p210 BCR/ABL1 transcript.

Forty-three patients were enrolled. Two patients who did not meet the eligibility criteria were excluded from the analyses. Then 41 patients were evaluable and included in the full analysis set. The median follow-up period was 48.5 months(1.0-84.3). As four out of 27 patients registered died of grade 5 adverse events (CTCAE v4.0), ALL-Ph13 was discontinued in May 2015 and amended to improve the safety in treatment. In November 2016, amended ALL-Ph13 was resumed. The registration was closed on November 30, 2017, and subsequently, the study was completed on November 30, 2020.

Adverse events were observed in all patients, with hematologic toxicity occurring more frequently. Seventy-four severe adverse events (>= grade 3 according to CTCAEv4.0) were reported. Four of them were grade 5 with a causal relationship with protocol treatment and caused the patients' death of sepsis. After the resumption of the protocol treatment, 16 patients were registered, but there were no severe adverse events.

As the primary endpoint in this study, the 3-year event-free survival rate (EFS) was 65.1% (95% CI: 48.3-77.6). Regarding the secondary endpoints, the 3-year overall survival rate was 85.1% (69.8-93.0), the complete remission (CR) plus CR in suppression rate at the end of IA was 92.7% (95% CI: 80.1-98.5), and CR rate at the end of IB was 100.0 (95% CI: 90.5-100). Furthermore, the 3-year overall survival rate of imatinib (n=33), dasatinib without SCT (n=7), and dasatinib with SCT (n=1) group were 87.7% (70.4-95.2), 71.4% (25.8-92.0), 100%, respectively. Although only one patient received SCT as the SCT group, six patients (14.6%) finally received SCT during the first CR. The number of patients with positive Ig/TCR PCR-MRD, FCM-MRD, and chimeric gene MRD decreased over time. The MRD disappearance rate by TP2 (the end of early consolidation therapy) was 61%, the MRD disappearance rate by TP5 (the end of consolidation therapy) was 87%, and the MRD recurrence rate was 7%. In OS, Ig/TCR MRD negative patients at TP2 showed higher survival rates than positive patients. Adverse events were as mentioned above.

The ALL-Ph13 was the first trial for Japanese children with Philadelphia chromosome-positive ALL in which TKIs were continuously administered with chemotherapy. Despite the limited use of SCT, this study showed more than 60% of the 3-year EFS. After the amendment of the protocol, the toxicities of the ALL-Ph13 were acceptable. The ALL-Ph13 showed comparable outcomes to other clinical trials using TKIs with chemotherapy.

April. 01, 2023

Feb. 25, 2026

https://pubmed.ncbi.nlm.nih.gov/41738671/

No

https://jrct.mhlw.go.jp/latest-detail/jRCTs041180144

Sato Atsushi

Miyagi Children's Hospital

4-3-17 Ochiai, Aoba-ku, Sendai, Miyagi

asatoh@miyagi-children.or.jp

Sato Atsushi

Miyagi Children's Hospital

4-3-17 Ochiai, Aoba-ku, Sendai, Miyagi

+81-22-391-5111

asatoh@miyagi-children.or.jp

Complete

Oct. 01, 2013

Interventional

single arm study

open(masking not used)

no treatment control/standard of care control

single assignment

treatment purpose

1) diagnosis of Ph+ALL
2) age between 1 and 19 years old
3) ECOG performance status (PS) score of 0-3
4) no history of previous chemotherapy or radiation therapy
5) written informed consent obtained from patient or guardians.

1) uncontrolled infection, including active tuberculosis and positive of HIV antibody.
2) pregnancy or high possibility of pregnancy and giving suck wiman.
3) history of congenital or acquired immunodeficiency.
4) any inappropriate status judged by
physician.

Both

Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Chemotherapy combined with imatinib or dasatinib.

Three years event free survival

1. 3 year overall survival (OS)
2. Three-year OS of imatinib group, no dasatinib transplant group, dasatinib transplant group
3. 3-year EFS of imatinib group, no dasatinib transplant group, dasatinib transplant group
4. Introduction rate of remission after completion of remission induction therapy (IA) combined with imatinib
5. Remission induction rate after completion of imatinib combination early strengthening therapy (IB), dasatinib combination early strengthening therapy (IB) and total early strengthening therapy (IB)
6. Temporal change of minute residual lesions (Ig / TCR PCR MRD, FCM MRD, chimeric gene MRD) of TKI combined chemotherapy
7. Relationship between long-term prognosis and MRD before transplant
8. Relation between BCR-ABL chimeric gene mutation and MRD disappearance rate / MRD recurrence rate
9. Relation between IKZF1 gene deletion and MRD disappearance rate, MRD recurrence rate
10. Search for prognostic factors by genome analysis, epigenome analysis, transcriptome analysis of Ph + ALL cells
11. Relationship between imatinib blood concentration and dasatinib blood concentration and MRD elimination rate , MRD recurrence rate
12. Relationship between Imatinib blood concentration and Dasatinib blood concentration and adverse events
13. Evaluation of patient QOL obtained by questionnaire survey by himself and family (surrogate evaluation)
14. Adverse Event Incidence
15. Implementation rate of transplant in the first remission phase

+81-52-951-1111

Jan. 24, 2019

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