Advances in the treatment of pediatric B-cell acute lymphoblastic leukemia with high-risk cytogenetics

doi:10.3969/j.issn.1674-8115.2025.10.015

Abstract

Abstract:

B-cell acute lymphoblastic leukemia (B-ALL) is one of the most common pediatric malignancies, characterized by highly heterogeneous genetic alterations. The precise identification of high-risk genetic abnormalities, such as BCR-ABL1, KMT2A rearrangement, and TCF3-HLF, plays a crucial role in risk stratification, the formulation of chemotherapy regimens, and the selection of individualized therapies. High-risk cytogenetics can profoundly impact the trajectory of disease progression and therapeutic outcomes. Regarding therapy, the refinement of treatment strategies through precise molecular classification and risk stratification has catalyzed a gradual paradigm shift in clinical practice. This transition moves away from the traditional reliance on conventional chemotherapy agents toward individualized pharmacotherapy and disease management strategies based on prognostic risk stratification. In recent years, immunotherapy has achieved significant progress in leukemia treatment. Chimeric antigen receptor T-cell (CAR-T) therapy and monoclonal antibodies have emerged as novel therapies for patients with relapsed/refractory (R/R) B-ALL harboring high-risk cytogenetic features. These innovations have significantly improved the prognosis for this patient population. Currently, new clinical trials are continuously advancing. Emerging targeted therapies and cell therapies represented by CAR-T cells have become hot spots of current research and have demonstrated remarkable development potential. This review synthesizes recent therapeutic advances across pediatric B-cell acute lymphoblastic leukemia subtypes harboring high-risk genetic abnormalities, with a focused emphasis on the evolving role of immunotherapy. By critically integrating current evidence, we aim to outline rational strategies for developing safer and more effective therapies that can meaningfully improve clinical outcomes in these high-risk children and adolescents.

Key words: B-cell acute lymphoblastic leukemia (B-ALL), high-risk cytogenetics, targeted therapy, immunotherapy, chimeric antigen receptor T-cell (CAR-T)

CLC Number:

R733.71

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.

Figures/Tables 1

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References 48

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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^[11]
		/	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^[13]
		/	ChiCTR-ONRC-14004968 ChiCTR2100042248 ChiCTR2100044308			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		LIU W Y, et al^[13]
	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 ^[19]
	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^[46]
	Proteasome inhibitors	Phase Ⅱ	UMIN000023815	Bortezomib combined with chemotherapy	R/R ALL children (15 B-ALL, 1 T-ALL)	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%		MIYAGAWA N, et al^[46]
	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^[47]
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^[27]
	CAR-T cells	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^[34]
	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 ^[48]
	Blinatumomab	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 ^[38]
	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^[44]

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^[11]
		/	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^[13]
		/	ChiCTR-ONRC-14004968 ChiCTR2100042248 ChiCTR2100044308			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		LIU W Y, et al^[13]
	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 ^[19]
	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^[46]
	Proteasome inhibitors	Phase Ⅱ	UMIN000023815	Bortezomib combined with chemotherapy	R/R ALL children (15 B-ALL, 1 T-ALL)	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%		MIYAGAWA N, et al^[46]
	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^[47]
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^[27]
	CAR-T cells	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^[34]
	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 ^[48]
	Blinatumomab	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 ^[38]
	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^[44]