Haploidentical hematopoietic stem cell transplantation as promising therapy in the improved survival of pediatric patients with leukemias and myelodysplasias

Table 1 Methodological aspects: General characteristics on the studies included

Ref.	Journal	Country	Study designs	Study analysis time	Objective
Kim et al[15], 2021	British Journal of Haematology	Korea	Retrospective	2009-2020	To analyze genetic abnormalities in JMML to evaluate the genetic profile of this rare paediatric leukaemia in a single Korean institution
Hong et al[16], 2022	Transplan tation and Cellular Therapy	Korea	Retrospective comparative	2013-2020	To compare outcomes in children and adolescents with high-risk acute leukemia after a busulfan-based myeloablative conditioning regimen along with HRD HSCT with PT-Cy or MUD HSCT
Bertaina et al[17], 2018	Blood	Italy	Retrospective	2010-2015	To report the outcome of children with acute leukemia who received either UD-HSCT or αβhaplo-HSCT
Bai et al[18], 2020	Leukemia Research	China	Retrospective	2008-2018	To investigate the clinical characteristics, outcomes, and effects of HSCT (especially haplo-HSCT) among non- infant children with t(v;11q23)/MLL-r B-ALL
Ruggeri et al[19], 2021	Transplan tation and Cellular Therapy	Italy	Prospective cohort	2011-2019	To analyze the outcomes of unmanipulated haploidentical Transplantation using PT-Cy in pediatric patients with acute lymphoblastic leukemia
Sun et al[20], 2015	European Review for Medi cal Pharmaco logical Sciences	China	Retrospective	2002-2012	To discuss the effect of transplantation and the difference in treatment effect among children having different donor patterns, aiming to identify the prognostic factors
Sano et al[21], 2021	Frontiers in pediatrics	Japan	Retrospective	2009-2019	To aimed to evaluate the efficacy of T-cell replete HLA-HSCT for pediatric RR-BCP-ALL
Paina et al[22], 2018	Cellular Therapy and Transplantation	Germany	Prospective cohort	2006-2016	To assess efficiency of haplo-HSCT performed with non-manipulated grafts of children and adolescents with high-risk acute leukemias. In this respect an efficiency study of haploidentical GVHD was performed at our clinic in children and adolescents with high-risk ALL and AML, at maximal observation terms of 10 years
Mo et al[23], 2016	Internatio nal Journal of Cancer	China	Retrospective comparative	2011-2015	To compare the therapeutic effects of single UCBT and unmanipulated haplo-HSCT in high-risk ALL children
Wang et al[24], 2020	Journal of Internatio nal Clinical Cytometr y Society	China	Prospective cohort	2011-2016	To determine the impact of pre- and post-MRD status as well as peri-transplant MRD kinetics on clinical outcomes focused on children with ALL who received haploidentical allografts
Zhang et al[25], 2022	Chinese Medical Journal	China	Retrospective comparative	2012-2018	To explore the effect of allo- HSCT (especially haploidentical HSCT) on improving survival and reducing relapse for high-risk childhood T-ALL in CR1 and the prognostic factors of childhood T-ALL in order to identify who could benefit from HSCT
Zheng et al[26], 2020	Cancer Communi cations	China	Retrospective comparative	2013-2017	To compare the survival outcomes between high-risk AML children who underwent either unmanipulated HID-SCT or ISD-SCT at three large Chinese SCT centers
Trujillo et al[27], 2021	American Society For Transplan tation and Celular Therapy	Colombia	Retrospective	2012-2017	To decrease the toxicity associated with the addition of 100 mg/kg of cyclophosphamide to a myeloablative regimen while maintaining a good antileukemic effect and a good engraftment rate, using an intermediate-intensity regimen
Yang et al[28], 2022	Hematology	China	Retrospective	2015-2021	To investigate the outcomes and prognostic factors of pediatric AML patients with KMT2A rearrangements who were treated at our institution over a 5-year period
Bai et al[29], 2022	BMC cancer	China	Retrospective	2014-2019	To explore the role of allo- HSCT (especially haploidentical-HSCT) in the treatment of paediatric patients with MLL-r AML in CR1 and investigated the prognostic factors of these patients
Miyamura et al[30], 2019	Leukemia Research	Japan	Retrospective	1988-2011	To investigate the outcomes and prognostic factors of AML with KMT2A rearrangement treated with allogeneic HSCT
Oevermann et al[32], 2014	Blood	Germany	Retrospective comparative	1996-2013	To analyze the influence of KIR haplotypes on the outcome of children with ALL given haploidentical HSCT
Pérez-Martínez et al[33], 2020	American Journal of Hematolo gy	Spain	Retrospective	1999-2016	To compare and analyze the feasibility and outcome of a Spanish cohort of 2 haplo-HSCT platforms in children and adolescents with high-risk hematological malignancies: PT-Cy and ex vivo TCD grafts

JMML: Juvenile myelomonocytic leukemia; HSCT: Hematopoietic stem cell transplantation; PT-Cy: Post-transplantation cyclophosphamide; MUD: Matched unrelated donors; RR-BCP: Relapsed or refractory B-cell precursor acute lymphoblastic leukemia; KIR: Killer cell immunoglobulin-like receptor; TCD: T cells; ALL: Acute lymphocytic leukemia.

Table 2 Characteristics of haploidentical transplants identified in the studies included

Ref.	All patients, n	Age, yr, median	Sex, male, n	Condition clinic	Haplo transplant cohort, n	Age, yr, median	Sex, male, n	Source of stem cells
Kim et al[15], 2021	24	1.201	15	JMML	14	NR	NR	PBSC
Hong et al[16], 2022	80	NR	51	ALL, AML, MPAL, and NK cell leukemia	35	7.00	22	PBSC
Bertaina et al[17], 2018	343	3.30	210	ALL, AML	98	6.60	65	PBSC5 BM
Bai et al[18], 2020	383	4.00	25	MLL-r B-ALL	194	4.00	13	NR
Ruggeri et al[19], 2021	180	9.25	114	ALL	180	9.25	114	PBSC BM
Sun et al[20], 2015	111	10.00	73	AML, ALL, CML, and MLL	111	10.00	73	PBSC BM
Sano et al[21], 2021	19	10.00	12	RR-BCP-ALL	19	10.00	12	PBSC, PB + BM
Paina et al[22], 2018	106	7.00	65	ALL, AML	106	7.00	65	BM + PBSC BM
Mo et al[23], 2016	129	NR	42	HR, ALL	65	10.00	33	G-BM, G-PB
Wang et al[24], 2020	166	15.00	114	B-ALL and T-ALL	166	15.00	114	NR
Zhang et al[25], 2022	74	11.00	52	HR T-ALL	272	12.00	21	BM
Zheng et al[26], 2020	82	NR	56	HR AML	69	12.00	42	PBSC, BM
Trujillo et al[27], 2021	42	11.00	24	ALL, AML, JMML, and CML	42	11.00	24	PBSC
Yang et al[28], 2022	21	NR	15	AML, KMT2A rearrangents	17	6.06	12	NR
Bai et al[29], 2022	44	9.00	25	MLL-r AML	37	NR	NR	NR
Miyamura et al[30], 2019	90	3.00	49	AML KMT2A rearrangents	10	NR	NR	NR
Oevermann et al[32], 2014	85	10.00	NR	ALL	85	10.00	NR	PBSC
Pérez-Martínez et al[33], 2020	192	8.60	118	ALL, AML, MDS, JMML, CML, and biphenotyipic	192	8.60	118	PBSC BM

¹In the study, this information was given in months.

²Four patients had a matched sibling donor. So, only 23 patients received haplo-hematopoietic stem cell transplantation. However, Zhang et al[25] didn’t give the age and numbers by sex separately.

³One patient was excluded from the analysis owing to death from pulmonary infection during induction. So, only 37 patients were analyzed.

⁴One patient received human leukocyte antigen-MUDT. So, only 18 received the haplo-transplant CR1. However, Bai et al[18] didn’t give the age and numbers by sex separately.

⁵All patients in the haplo cohort received stem cells from peripheral blood stem cells.

JMML: Juvenile myelomonocytic leukemia; ALL: Acute lymphocytic leukemia; AML: Acute myeloid leukemia; CML: Chronic myelogenous leukemia; MLL: Mixed lineage leukemia; MPAL: Mixed-phenotype acute leukemia; NK: Natural Killer; RR-BCP: Relapsed or refractory B-cell precursor acute lymphoblastic leukemia; NR: Not related; PBSC: Peripheral blood stem cells; BM: Bone marrow; PB: Peripheral blood.

Table 3 Conditioning, event-free survival and overall survival of the analyzed patients

Ref.	Haplo transplant cohort, n	Conditioning regimens (all cohorts)				Haplo cohort
		I	II	III	IV	EFS (%)	OS (%)
Kim et al[15], 2021	14	MAC: Bu-Flu	MAC: Bu-Flu-TBI	RIC: Bu-Flu-TBI	-	NRS	NRS
Hong et al[16], 2022	35	MAC, Bu, Flu	MAC, Bu, Flu, and Cy	TBI after blinatumomab	-	74.4% (3 years)	88.6% (3 years)
Bertaina et al[17], 2018	98	MAC: Bu	MAC/TBI: TBI-based	Treosulfan based	-	62.0% (5 years)	68.0% (5 years)
Bai et al[18], 2020	181, 087	MAC/chemo: Cytarabine, Cy, Bu, and semustine	-	-	-	89.5% (4 years), NRS	87.4% (4 years); 57.1% (4 years)
Ruggeri et al[19], 2021	180	MAC/chemo	MAC/TBI	RIC	-	38.5%2 (2 years); 65%3; 44%4, and 18.8%5	50.8% (2 years); 76.5%7; 61.2%7; (NRS)
Sun et al[20], 2015	111	MAC: Bu, cycytarabine, and Me-CCNU	MAC/TBI Cy, cytarabine	-	-	79.2% (5 years)	NR
R	19	MAC: Bu, Flu, and melphalan, TBI-based	MAC: Bu-based	RIC	-	42.1% (3 years)	57.4% (3 years)
Paina et al[22], 2018	106	MAC: Bu, Cy, and Lomustin	MAC, Bu-flu	MAC: Treosulfan	RIC: Melphalan; RIC: Bu	NR	33.3% (10 years); 64.7%; 18.1%, (10 years)6
Mo et al[23], 2016	65	Cytarabine, Bu, Cy, and semustine	TBI	MAC: Bu-Flu Carmustine	MAC: CyFlu-TBI	71% (2 years)	82.0% (2 years)
Wang et al[24], 2020	166	RIC: Cy, MTX, MMF	-	-	-	60.2% (100 d)	60.8% (100 d)
Zhang et al[25], 2022	23	MAC: Bu-Cy, hydroxyurea cytarabine, and methy	-	-	-	80.1% (5 years)	81.0% (5 years)
Zheng et al[26], 2020	69	Bu-Cy, cytarabine, semustine	Bu-Cy-Hu, cytarabine, semustine	-	-	72.9% (3 years)	73.0% (3 years)
Trujillo et al[27], 2021	42	RIC: Bu-Flu-TBI	RIC: Flu-Mel-TBI	-	-	46% (3 years)	56% (3 years)
Yang et al[28], 2022	17	Cytarabine, Bu, and Cy Me-CCNU	Cytarabine, Bu-Cy	-	-	NRS	NRS
Bai et al[29], 2022	37	Cytarabine, Bu-Cy, and semustine	-	-	-	65.6% (3 years)	73.0% (3 years)
Miyamura et al[30], 2019	10	MAC, Bu-TBI	RIC, NR	-	-	NRS	NRS
Oevermann et al[32], 2014	85	TBI	Non TBI	-	-	50.6%7 (5 years); 29.5%7 (5 years)	NR
Pérez-Martínez et al[33]	192	Flu-Thiotepa-Mel or Bu	TLI or TBI	-	-	49.2% (2 years)	55.1% (2 years)

¹In the study, 18 patients in the complete remission 1 (CR1) e 8 other patients from the other cohort experiencing relapse opted for allogeneic hematopoietic stem cell transplantation (HSCT, CR2, n = 13, but just 8 patients opted for allogeneic HSCT).

²General.

³CR1.

⁴CR2.

⁵CR3.

⁶CR1 and CR2; patients transplanted beyond the remission.

⁷KIR B haplotype; KIR A haplotype.

NRS: Not reported separately; NR: Not reported; TLI: Traumatic lung injury; TBI: Total body irradiation; MAC: Myeloablative conditioning regimen; RIC: Reduced intensity regimen.