Newly-diagnosed Low Risk Pediatric B-cell ALL Protocol

Официальное название

Chinese Children's Cancer Group-2025 Protocol for Newly Diagnosed Low Risk Childhood B-cell Acute Lymphoblastic Leukemia

Обзор

CCCG-ALL2025 LR-B-ALL plan is designed based on the CCCG-ALL2020 plan. This is a clinical trial using 14 days of blinatumomab (Blina-14) as early intensification after induction therapy and 2nd Blina-14 in consolidation therapy in all newly diagnosed provisional low-risk (LR) pediatric acute lymphoblastic leukemia (ALL) patients, regardless of measurable residual diseases (MRD) status. We will compare the efficacy of chemotherapy combined with Blina-14, comparing to CAT+ intensification or historical regimens. Patients with early remission in depth will receive chemo-light late intensification and maintenance therapy afterwards. Early complete remission in depth and maintenance reduction will be determined by next-generation sequencing (Ig-NGS MRD).

Подробное описание

1. All LR-B-ALL patients will be treated with 14 days of blinatumomab (Blina-14) as early intensification to replace CAT+ (historically given in LR-B-AL with MRD19\>0.1% in the 2020 protocol). 2. Two courses of HD-MTX will be administered as consolidation phase, maintaining the same dose of 3 g/m². 3. Second 14 days of blinatumomab will be given after completion of HDMTX consolidation treatment . 4. Adding IgH rearrangement NGS MRD as an evaluation indicator. Reinduction-2 will be omitted for patients with NGS-MRD46\<10-6 who have receive the second course of Blina-14. (Reinduction-2 should be given regardless of NGS-MRD 46 status in patients who did not receive the second course of binatumomab). 5. A total of four repeating courses will be applied in Maintenance 1 (in contrast to 5 courses in 2020 protocol). Additionally, one-week rest period will be implemented after each course to ensure safety and optimal efficacy. 6. Patients with FCM-MRD19\<0.01% and IgH rearrangement NGS MRD 46\<10-6 will receive chemo-light maintenance-2 with 4 cyles of 8-week course of MTX + 6MP (totally 32 weeks). The other patients with higher levels of MRD by FCM MRD or NGS MRD will receive maintenance-2 with 9 cycles of 8-week course of MTX + 6MP for a total of 72 weeks (same as CCCG-ALL2020) 7. Bone Marrow Aspiration Assessment (BMA): One additional bone marrow puncture at the end of 1st Blina-14 course (Day60 MRD) will be performed at early intensification phase. This results in a total of 4 BMAs in the CCCG2025-LR protocol, in contrast to 3 BMAs in 2020 protocol. 8. Triple Intrathecal Therapy (TIT)：In the HDMTX consolidation phase, there will be two TITs in contrast to four treatments in the CCCG2020 protocol. To compensate for this reduction, two additional TIT treatments will be administrated before the 1st and 2nd Blina-14 courses. Additionally, two intrathecal treatments will be added during Reinduction 1 and Reinduction 2 to further enhance CNS control. Meanwhile, one TIT will be reduced in the Maintenance-1 phase compared to 2020 protocol. This results in a total of 16 or 17 TITs, depending on whether the second Blina-14 course is applied This is similar to the CCCG2020, where 16 or 17 TITs are administrated depending on whether CAT+ was given). 9. Adding pharmacotyping study for LR B-ALL. 10. Treatment duration: The treatment duration for the CCCG-LR-ALL-2020 protocol is 121/124 weeks (depending on if CAT+ was given). In the CCCG-LR-ALL-2025 protocol:

* For patients with NGS MRD46 ≥10-6, the total treatment duration is 123 weeks. Key changes include: 2 weeks of Blina-14 replacing 3 weeks of CAT+, 2 courses of HDMTX reduction (4 weeks), and an additional 2 weeks for the 2nd blina-14 course added following HDMTX; * For patients with MRD19≥ 0.01% and NGS MRD46 \< 10-6 who subsequently receive 2nd Blina-14, Reinduction-2 is omitted, shortening the total duration by 3 weeks. (120 weeks in total). If the 2nd Blina-14 is not administrated, Reinduction -2 will still be included, resulting in a total duration of 121 weeks. * For patients with MRD19 \< 0.01% and NGS MRD46 \< 10-6, who subsequently receive 2nd Blina-14, both the Reinduction-2 (3 weeks) and the subsequent 5 cycles of Maintenance-2 (40 weeks) are omitted. This results in a total treatment duration of 80 weeks (81 weeks if 2nd Blina-14 is not applied).

Вмешательства

• Препарат Blinatumomab
  All LR-B-ALL patients will be treated with 14 days of blinatumomab (Blina-14) as early intensification to replace CAT+ (historically given in LR-B-AL with MRD19\>0.1% in the 2020 protocol). Additionally, second 14 days of blinatumomab will be given after completion of HDMTX consolidation treatment.
• Препарат Reinduction-2 omission
  Reinduction-2 will be omitted for patients with NGS-MRD46\<10\^-6 who have receive the two courses of Blina-14.
• Препарат Chemo-light Maintenance 2
  Patients with FCM-MRD19\<0.01% and IgH rearrangement NGS MRD 46\<10\^-6 will receive chemo-light maintenance-2 with 4 cyles of 8-week course of MTX + 6MP (totally 32 weeks).

Первичные конечные точки

• Compare 3-year event-free survival (EFS) between patients who receive Blina-14 intensification with this historical controls from CCCG-ALL2015 and CCCG-ALL2000 [Срок оценки: The expected study duration is approximately 5 years.]

Вторичные конечные точки (9)

• Estimate event-free survival (EFS) in patients with deep remission (FCM MRD19<0.01% and Ig-NGS MRD46<10-6) who received Maintenance-2' with reduced intensity chemotherapy [Срок оценки: Approximately 6.5 years.]
• Estimate overall survival (OS) in patients with deep remission (FCM MRD19<0.01% and Ig-NGS MRD46<10-6) who received Maintenance-2' with reduced intensity chemotherapy [Срок оценки: Approximately 6.5 years.]
• Estimate cumulative incidence of relapse (CIR) in patients with deep remission (FCM MRD19<0.01% and Ig-NGS MRD46<10-6) who received Maintenance-2' with reduced intensity chemotherapy [Срок оценки: Approximately 6.5 years.]
• Compare event-free survival (EFS) to those of historical cohorts (CCCG-ALL-2015 and CCCG-ALL2020) [Срок оценки: Approximately 6.5 years.]
• Compare overall survival (OS) to those of historical cohorts (CCCG-ALL-2015 and CCCG-ALL2020) [Срок оценки: Approximately 6.5 years.]
• Compare cumulative incidence of relapse (CIR) to those of historical cohorts (CCCG-ALL-2015 and CCCG-ALL2020) [Срок оценки: Approximately 6.5 years.]
• Compare event-free survival (EFS) between patients with deepen remission (FCM MRD19<0.01% and Ig-NGS MRD46<10-6) who receive one course of Blina-14 and those who recevive two courses of Blina-14. [Срок оценки: Approximately 6.5 years]
• Compare overall survival (OS) between patients with deepen remission (FCM MRD19<0.01% and Ig-NGS MRD46<10-6) who receive one course of Blina-14 and those who recevive two courses of Blina-14. [Срок оценки: Approximately 6.5 years]
• Compare cumulative incidence of relapse (CIR) between patients with deepen remission (FCM MRD19<0.01% and Ig-NGS MRD46<10-6) who receive one course of Blina-14 and those who recevive two courses of Blina-14. [Срок оценки: Approximately 6.5 years]

Критерии участия

Критерии включения

Must meet all items below:

• Age older than 1 year and younger than 18 years.
• Diagnosis of acute lymphoblastic leukemia by bone marrow morphology.
• Diagnosis of B-ALL by immunophenotyping.
• Low risk group

Критерии исключения

Should be excluded in the presence of any item below:

• T-ALL
• I/HR B-ALL group
• sIgM+
• Acute leukemias of ambiguous lineage diagnosed according to WHO or EGIL criteria.
• Philadelphia chromosome positive ALL (Ph-ALL)
• ALL evolved from chronic myeloid leukemia (CML).
• Down's syndrome, or major congenital or hereditary disease with organ dysfunction
• Secondary leukemia
• Known underlying congenital immunodeficiency or metabolic disease
• Congenital heart disease with cardiac insufficiency.
• Glucocorticoid treatment for ≥14 days, or ABL kinase inhibitors for > 7 days within one month before enrollment, or any chemotherapy or radiotherapy within 3 months before enrollment (except for emergency radiotherapy to relieve airway compression)

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Факторный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 26 центров

• Anhui Medical University Second Affiliated Hospital — Хэфэй
• Anhui Provincial Children's Hospital — Хэфэй
• Chongqing Medical University Affiliated Children's Hospital — Чунцин
• Fujian Medical University Union Hospital — Фучжоу
• Guangzhou Women and Children's Medical Center — Гуанчжоу
• Nanfang Hospital, Southern Medical University — Гуанчжоу
• The People's Hospital of Guangxi Zhuang Autonomous Region — Nanning
• The Affiliated Hospital of Guizhou Medical University — Guiyang
• … и ещё 18 центров

Гонконг · 1 центр

• Hong Kong Children's Hospital — Гонконг

Публикации

• Lee SHR, Yang W, Gocho Y, John A, Rowland L, Smart B, Williams H, Maxwell D, Hunt J, Yang W, Crews KR, Roberts KG, Jeha S, Cheng C, Karol SE, Relling MV, Rosner GL, Inaba H, Mullighan CG, Pui CH, Evans WE, Yang JJ. Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response. Nat Med. 2023 Jan;29(1):170-179. doi: 10.1038/s41591-022-02112-7. PMID 36604538
• Chen H, Gu M, Liang J, Song H, Zhang J, Xu W, Zhao F, Shen D, Shen H, Liao C, Tang Y, Xu X. Minimal residual disease detection by next-generation sequencing of different immunoglobulin gene rearrangements in pediatric B-ALL. Nat Commun. 2023 Nov 17;14(1):7468. doi: 10.1038/s41467-023-43171-9. PMID 37978187
• Hengeveld PJ, van der Klift MY, Kolijn PM, Davi F, Kavelaars FG, de Jonge E, Robrecht S, Assmann JLJC, van der Straten L, Ritgen M, Westerweel PE, Fischer K, Goede V, Hallek M, Levin MD, Langerak AW. Detecting measurable residual disease beyond 10-4 by an IGHV leader-based NGS approach improves prognostic stratification in CLL. Blood. 2023 Feb 2;141(5):519-528. doi: 10.1182/blood.2022017411. PMID 36084320
• Svaton M, Skotnicova A, Reznickova L, Rennerova A, Valova T, Kotrova M, van der Velden VHJ, Bruggemann M, Darzentas N, Langerak AW, Zuna J, Stary J, Trka J, Fronkova E. NGS better discriminates true MRD positivity for the risk stratification of childhood ALL treated on an MRD-based protocol. Blood. 2023 Feb 2;141(5):529-533. doi: 10.1182/blood.2022017003. PMID 36240445
• Li Z, Jiang N, Lim EH, Chin WHN, Lu Y, Chiew KH, Kham SKY, Yang W, Quah TC, Lin HP, Tan AM, Ariffin H, Yang JJ, Yeoh AE. Identifying IGH disease clones for MRD monitoring in childhood B-cell acute lymphoblastic leukemia using RNA-Seq. Leukemia. 2020 Sep;34(9):2418-2429. doi: 10.1038/s41375-020-0774-4. Epub 2020 Feb 25. PMID 32099036
• Foa R, Bassan R, Elia L, Piciocchi A, Soddu S, Messina M, Ferrara F, Lunghi M, Mule A, Bonifacio M, Fracchiolla N, Salutari P, Fazi P, Guarini A, Rambaldi A, Chiaretti S. Long-Term Results of the Dasatinib-Blinatumomab Protocol for Adult Philadelphia-Positive ALL. J Clin Oncol. 2024 Mar 10;42(8):881-885. doi: 10.1200/JCO.23.01075. Epub 2023 Dec 21. PMID 38127722
• Hogan LE, Brown PA, Ji L, Xu X, Devidas M, Bhatla T, Borowitz MJ, Raetz EA, Carroll A, Heerema NA, Zugmaier G, Sharon E, Bernhardt MB, Terezakis SA, Gore L, Whitlock JA, Hunger SP, Loh ML. Children's Oncology Group AALL1331: Phase III Trial of Blinatumomab in Children, Adolescents, and Young Adults With Low-Risk B-Cell ALL in First Relapse. J Clin Oncol. 2023 Sep 1;41(25):4118-4129. doi: 10.1200/J PMID 37257143
• Litzow MR, Sun Z, Mattison RJ, Paietta EM, Roberts KG, Zhang Y, Racevskis J, Lazarus HM, Rowe JM, Arber DA, Wieduwilt MJ, Liedtke M, Bergeron J, Wood BL, Zhao Y, Wu G, Chang TC, Zhang W, Pratz KW, Dinner SN, Frey N, Gore SD, Bhatnagar B, Atallah EL, Uy GL, Jeyakumar D, Lin TL, Willman CL, DeAngelo DJ, Patel SB, Elliott MA, Advani AS, Tzachanis D, Vachhani P, Bhave RR, Sharon E, Little RF, Erba HP, PMID 39047240

Идентификаторы

NCT: NCT06882057 · IIT2025021

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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