上海交通大学学报（医学版） ›› 2025, Vol. 45 ›› Issue (10): 1390-1399.doi: 10.3969/j.issn.1674-8115.2025.10.015
唐珺倩, 李本尚(
)
收稿日期:2025-03-25
接受日期:2025-06-19
出版日期:2025-10-28
发布日期:2025-10-23
通讯作者:
李本尚，主任医师，博士；电子信箱：libenshang@scmc.com.cn。
TANG Junqian, LI Benshang()
Received:2025-03-25
Accepted:2025-06-19
Online:2025-10-28
Published:2025-10-23
Contact:
LI Benshang, E-mail: libenshang@scmc.com.cn.摘要：
B系急性淋巴细胞白血病（B-cell acute lymphoblastic leukemia，B-ALL）是儿童最常见的恶性肿瘤之一，其特点是具有高度异质性的遗传学改变。对BCR-ABL1、KMT2A重排、TCF3-HLF等高危遗传学异常的精准识别，在疾病的风险分层、化学治疗（化疗）方案的制定以及个体化用药的抉择等方面发挥着关键作用。高危遗传学异常显著影响疾病的进展态势与治疗转归。从治疗视角来看，通过精细的分子分类和风险分层，治疗策略得以优化，促使临床治疗实践从既往单纯依赖传统化疗药物，逐步转变为依据预后风险分层实施个体化用药及疾病管理模式。近年来，免疫治疗在白血病中取得了显著进展，嵌合抗原受体T细胞（chimeric antigen receptor T-cell，CAR-T细胞）、单克隆抗体等为复发/难治（relapsed/refractory，R/R）的高风险B-ALL患儿提供了新的治疗选择，大幅改善了预后。当前，新的临床试验正持续推进，新兴的靶向治疗以及以CAR-T细胞为代表的细胞免疫治疗是当下的研究热点，展现出巨大的发展潜力。该文综述了儿童伴高风险遗传学异常的各亚型B-ALL在治疗方面的研究进展，并重点讨论目前免疫疗法在其中的应用潜能，以期为制定更有效、更安全的治疗方案从而改善疾病预后提供线索和思路。
中图分类号:
唐珺倩, 李本尚. 儿童高危细胞遗传学B系急性淋巴细胞白血病治疗新进展[J]. 上海交通大学学报（医学版）, 2025, 45(10): 1390-1399.
TANG Junqian, LI Benshang. Advances in the treatment of pediatric B-cell acute lymphoblastic leukemia with high-risk cytogenetics[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(10): 1390-1399.
| Therapeutic approach | Representative drug | Clinical trial name/phase | Clinical trial registration number | Treatment | Participant | Short-term efficacy | Long-term efficacy | Safety | Reference |
|---|---|---|---|---|---|---|---|---|---|
| Small molecule inhibitors | TKI | CA180-372/COG AALL1122 Phase Ⅱ | NCT01460160 | Dasatinib combined with intensive chemotherapy | Newly diagnosed Ph+ ALL children (104 B-ALL, 2 T-ALL) | CR rate 100% | 3-year EFS 65.5%, OS 91.5%; 5-year EFS 54.6%, OS 81.7%; 36% patients relapsed (38/106) | No deaths due to Dasatinib. 8% died from treatment-related complications (mainly infections) | HUNGER S P, et al[ |
| / | ChiCTR-ONRC-14004968 ChiCTR2100042248 ChiCTR2100044308 | Olverembatinib (compassionate use, combined with chemotherapy; 8 patients underwent allo-HSCT and continued Olverembatinib maintenance therapy until disease progression or intolerable toxicity) | Ph+ ALL with T315I mutation or relapsed/refractory disease in adult patients | 14 cases of relapsed/refractory disease (10 with T315I mutation): ORR 71.4%; 42.9% MRD negative; 35.7% complete molecular remission | Median EFS 3.9 months; median OS 8.3 months | 71% experienced grade 3‒4 treatment-related adverse events; No permanent Olverembatinib discontinuation | LIU W Y, et al[ | ||
| 17 cases of CR with MRD positivity (14 with T315I mutation): 60% MRD negative; 47.1% complete molecular remission | Median EFS 11.5 months; median OS 18.4 months | ||||||||
| Menin inhibitors | AUGMENT-101 Phase Ⅱ | NCT04065399 | Revumenib | R/R KMT2A-R acute leukemia (49 AML, 7 ALL, 1 mixed lineage acute leukemia) in children and adults | CR+CRh rate 22.8%; ORR 63.2% (68.2% MRD negative) | Median OS 8.0 months | 14.9% died from treatment-related adverse events | ISSA G C, et al [ | |
| Proteasome inhibitors | Phase Ⅱ | UMIN000023815 | Bortezomib combined with chemotherapy | R/R ALL children (15 B-ALL, 1 T-ALL) | 10 cases of high-risk first-relapse cohort (including 1 T-ALL): CR rate 60%, no patient achieved PR; MRD all positive | 4-month EFS 30%; 4-month OS 100% | 1 case died from interstitial lung disease and hypoxemia; other adverse events were reversible | MIYAGAWA N, et al[ | |
| 6 cases in the expansion cohort (including refractory ALL, multiple relapses, post-transplant relapse, and induction failure): CR rate 16.7%; PR rate 16.7%; MRD all positive | 4-month EFS 33.3%; 4-month OS 83.3% | ||||||||
| mTOR inhibitors | TACL 2014-001 Phase Ⅰ | NCT01614197 | Temsirolimus combined with cyclophosphamide and etoposide | R/R ALL children (10 B-ALL with high-risk cytogenetic abnormalities including KMT2A-R, Ph+, Ph-like; 5 T-ALL) | B-ALL children: overall response rate 40% (4/10); CR rate 20% (2/10); 2 cases MRD negative | / | 1 case with dose-limiting toxicity (grade 4 pleural effusion and pericardial effusion); other toxicities were reversible | TASIAN S K, et al[ | |
| Immunotherapy | CAR-T cells | / | NCT01626495 NCT02435849 NCT02374333 NCT02228096 NCT02906371 | CD19-directed CAR T-cell | Children and young adults with R/R B-ALL, high-risk cytogenetic abnormalities including KMT2A-R, Ph+, Ph-like, hypodiploidy, TCF3-HLF | CR rate 93%: KMT2A-R 92%; Ph+ 100%; Ph-like 84%; hypodiploidy 100%; TCF3/HLF 100%; iAMP21 100% | 2-year EFS 59%; 2-year RFS 63%; 2-year cumulative relapse rate 33%; 2-year OS 70% | / | LEAHY A B, et al[ |
| Phase Ⅱ | ChiCTR2000032211 | Coadministration of CD19- and CD22-directed CAR-T cell | 225 children with R/R B-ALL, high-risk cytogenetic abnormalities including Ph+, TCF3-HLF, KMT2A-R, MEF2D-R, iAMP21, ZNF384 | CR rate 99.1%; all patients with bone marrow involvement achieved MRD-negative remission | 12-month EFS 75.4%; 12-month OS 88.3% | Grade 3 or higher CRS incidence 28.4%, ICANS 4%; 3 deaths (1.33%) | WANG T Y, et al[ | ||
| Blinatumomab | Phase Ⅱ | EudraCT number 2016-004674-17 | Interfant-06 induction chemotherapy combined with Blinatumomab for 1 course (4-week continuous infusion), followed by Interfant-06 chemotherapy; 14 patients underwent HSCT | 30 newly diagnosed infants with KMT2A-R ALL | 93% achieved MRD negativity or <0.05% after Blinatumomab infusion; All the patients who continued chemotherapy became MRD-negative during further treatment | 2-year DFS 81.6%; 2-year OS 93.3% | No deaths or permanent discontinuation of Blinatumomab due to toxicity | VAN DER SLUIS I M, et al [ | |
| Phase Ⅱ | NCT05557110 | Reduced-dose induction chemotherapy followed by blinatumomab treatment for 2-4 weeks, extended to 4 weeks for patients who did not achieve CR/CRi after 2 weeks, as a first-line induction therapy regimen | 35 newly diagnosed Ph- B-ALL children and adult patients; 17 patients (49%) with high-risk cytogenetic abnormalities | 2 weeks of Blinatumomab treatment: 94% (33/35) achieved CR/CRi; 86% (30/35) achieved MRD negativity; 4 weeks of Blinatumomab treatment: 2 patients extended Blinatumomab treatment to 4 weeks; all 35 patients achieved CR, 89% (31/35) achieved MRD negativity | 1-year OS 97.1%; 1-year PFS 82.2%; 4 relapses: 1 case of isolated CNS relapse, 1 case of hematologic relapse, 2 cases of MRD-positive relapse; 3 cases were CD19-positive, and 1 case was CD19-negative. | ICANS: 14% (5/35), all grade 1. CRS: grade 3 or higher 9%. No treatment-related deaths | LU J, et al [ | ||
| InO | ITCC-059 Phase Ⅱ | EudraCT number 2016-000227-71; NTR5736 | InO as single agent | 27 pediatric patients with R/R B-ALL and high-risk cytogenetic abnormalities,including hypodiploidy and KMT2A-R | ORR 81.5%, with 81.8% MRD negative | 1-year EFS 36.7%; 1-year OS 55.1% | 71.4% experienced grade 3‒4 treatment-related adverse events; no treatment-related deaths | PENNESI E, et al[ |
表1 近3年部分药物临床试验结果概览
Tab 1 Overview of clinical trial results of selected drugs in the past 3 years
| Therapeutic approach | Representative drug | Clinical trial name/phase | Clinical trial registration number | Treatment | Participant | Short-term efficacy | Long-term efficacy | Safety | Reference |
|---|---|---|---|---|---|---|---|---|---|
| Small molecule inhibitors | TKI | CA180-372/COG AALL1122 Phase Ⅱ | NCT01460160 | Dasatinib combined with intensive chemotherapy | Newly diagnosed Ph+ ALL children (104 B-ALL, 2 T-ALL) | CR rate 100% | 3-year EFS 65.5%, OS 91.5%; 5-year EFS 54.6%, OS 81.7%; 36% patients relapsed (38/106) | No deaths due to Dasatinib. 8% died from treatment-related complications (mainly infections) | HUNGER S P, et al[ |
| / | ChiCTR-ONRC-14004968 ChiCTR2100042248 ChiCTR2100044308 | Olverembatinib (compassionate use, combined with chemotherapy; 8 patients underwent allo-HSCT and continued Olverembatinib maintenance therapy until disease progression or intolerable toxicity) | Ph+ ALL with T315I mutation or relapsed/refractory disease in adult patients | 14 cases of relapsed/refractory disease (10 with T315I mutation): ORR 71.4%; 42.9% MRD negative; 35.7% complete molecular remission | Median EFS 3.9 months; median OS 8.3 months | 71% experienced grade 3‒4 treatment-related adverse events; No permanent Olverembatinib discontinuation | LIU W Y, et al[ | ||
| 17 cases of CR with MRD positivity (14 with T315I mutation): 60% MRD negative; 47.1% complete molecular remission | Median EFS 11.5 months; median OS 18.4 months | ||||||||
| Menin inhibitors | AUGMENT-101 Phase Ⅱ | NCT04065399 | Revumenib | R/R KMT2A-R acute leukemia (49 AML, 7 ALL, 1 mixed lineage acute leukemia) in children and adults | CR+CRh rate 22.8%; ORR 63.2% (68.2% MRD negative) | Median OS 8.0 months | 14.9% died from treatment-related adverse events | ISSA G C, et al [ | |
| Proteasome inhibitors | Phase Ⅱ | UMIN000023815 | Bortezomib combined with chemotherapy | R/R ALL children (15 B-ALL, 1 T-ALL) | 10 cases of high-risk first-relapse cohort (including 1 T-ALL): CR rate 60%, no patient achieved PR; MRD all positive | 4-month EFS 30%; 4-month OS 100% | 1 case died from interstitial lung disease and hypoxemia; other adverse events were reversible | MIYAGAWA N, et al[ | |
| 6 cases in the expansion cohort (including refractory ALL, multiple relapses, post-transplant relapse, and induction failure): CR rate 16.7%; PR rate 16.7%; MRD all positive | 4-month EFS 33.3%; 4-month OS 83.3% | ||||||||
| mTOR inhibitors | TACL 2014-001 Phase Ⅰ | NCT01614197 | Temsirolimus combined with cyclophosphamide and etoposide | R/R ALL children (10 B-ALL with high-risk cytogenetic abnormalities including KMT2A-R, Ph+, Ph-like; 5 T-ALL) | B-ALL children: overall response rate 40% (4/10); CR rate 20% (2/10); 2 cases MRD negative | / | 1 case with dose-limiting toxicity (grade 4 pleural effusion and pericardial effusion); other toxicities were reversible | TASIAN S K, et al[ | |
| Immunotherapy | CAR-T cells | / | NCT01626495 NCT02435849 NCT02374333 NCT02228096 NCT02906371 | CD19-directed CAR T-cell | Children and young adults with R/R B-ALL, high-risk cytogenetic abnormalities including KMT2A-R, Ph+, Ph-like, hypodiploidy, TCF3-HLF | CR rate 93%: KMT2A-R 92%; Ph+ 100%; Ph-like 84%; hypodiploidy 100%; TCF3/HLF 100%; iAMP21 100% | 2-year EFS 59%; 2-year RFS 63%; 2-year cumulative relapse rate 33%; 2-year OS 70% | / | LEAHY A B, et al[ |
| Phase Ⅱ | ChiCTR2000032211 | Coadministration of CD19- and CD22-directed CAR-T cell | 225 children with R/R B-ALL, high-risk cytogenetic abnormalities including Ph+, TCF3-HLF, KMT2A-R, MEF2D-R, iAMP21, ZNF384 | CR rate 99.1%; all patients with bone marrow involvement achieved MRD-negative remission | 12-month EFS 75.4%; 12-month OS 88.3% | Grade 3 or higher CRS incidence 28.4%, ICANS 4%; 3 deaths (1.33%) | WANG T Y, et al[ | ||
| Blinatumomab | Phase Ⅱ | EudraCT number 2016-004674-17 | Interfant-06 induction chemotherapy combined with Blinatumomab for 1 course (4-week continuous infusion), followed by Interfant-06 chemotherapy; 14 patients underwent HSCT | 30 newly diagnosed infants with KMT2A-R ALL | 93% achieved MRD negativity or <0.05% after Blinatumomab infusion; All the patients who continued chemotherapy became MRD-negative during further treatment | 2-year DFS 81.6%; 2-year OS 93.3% | No deaths or permanent discontinuation of Blinatumomab due to toxicity | VAN DER SLUIS I M, et al [ | |
| Phase Ⅱ | NCT05557110 | Reduced-dose induction chemotherapy followed by blinatumomab treatment for 2-4 weeks, extended to 4 weeks for patients who did not achieve CR/CRi after 2 weeks, as a first-line induction therapy regimen | 35 newly diagnosed Ph- B-ALL children and adult patients; 17 patients (49%) with high-risk cytogenetic abnormalities | 2 weeks of Blinatumomab treatment: 94% (33/35) achieved CR/CRi; 86% (30/35) achieved MRD negativity; 4 weeks of Blinatumomab treatment: 2 patients extended Blinatumomab treatment to 4 weeks; all 35 patients achieved CR, 89% (31/35) achieved MRD negativity | 1-year OS 97.1%; 1-year PFS 82.2%; 4 relapses: 1 case of isolated CNS relapse, 1 case of hematologic relapse, 2 cases of MRD-positive relapse; 3 cases were CD19-positive, and 1 case was CD19-negative. | ICANS: 14% (5/35), all grade 1. CRS: grade 3 or higher 9%. No treatment-related deaths | LU J, et al [ | ||
| InO | ITCC-059 Phase Ⅱ | EudraCT number 2016-000227-71; NTR5736 | InO as single agent | 27 pediatric patients with R/R B-ALL and high-risk cytogenetic abnormalities,including hypodiploidy and KMT2A-R | ORR 81.5%, with 81.8% MRD negative | 1-year EFS 36.7%; 1-year OS 55.1% | 71.4% experienced grade 3‒4 treatment-related adverse events; no treatment-related deaths | PENNESI E, et al[ |
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