Outcomes of pediatric acute myeloid leukemia patients with FLT3-ITD mutations in the pre-FLT3 inhibitor era

Sujin Choi; Bo Kyung Kim; Hong Yul Ahn; Kyung Taek Hong; Jung Yoon Choi; Hee Young Shin; Hyoung Jin Kang

doi:10.5045/br.2020.2020127

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Original Article

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Blood Res 2020; 55(4):

Published online December 31, 2020

https://doi.org/10.5045/br.2020.2020127

Outcomes of pediatric acute myeloid leukemia patients with FLT3-ITD mutations in the pre-FLT3 inhibitor era

Sujin Choi¹, Bo Kyung Kim^1,2, Hong Yul Ahn^1,2, Kyung Taek Hong^1,2, Jung Yoon Choi^1,2, Hee Young Shin^1,2, Hyoung Jin Kang^1,2,3

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¹Department of Pediatrics, Seoul National University Children’s Hospital, Seoul National University College of Medicine, ²Seoul National University Cancer Research Institute, Seoul, ³Wide River Institute of Immunology, Hongcheon, Korea

Correspondence to : Hyoung Jin Kang, M.D., Ph.D.
Department of Pediatrics, Seoul National University Children’s Hospital, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
E-mail: kanghj@snu.ac.kr

Received: June 4, 2020; Revised: September 29, 2020; Accepted: October 16, 2020

Abstract

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Abstract

Background
Acute myeloid leukemia (AML) with internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD) is associated with poor outcomes. This study aimed to analyze the outcomes of pediatric AML patients with FLT3-ITD mutations in the pre-FLT3 inhibitor era.
Methods
We retrospectively reviewed and identified 18 patients diagnosed with non-M3 AML with FLT3-ITD mutations at Seoul National University Children’s Hospital between May 2008 and August 2019.
Results
The median age was 13 years (range, 6-19 yr). The median follow-up time was 43 months (range, 6-157 mo). Fourteen patients received BH-AC-based (N4-Behenoy1-1-b-D-arabinofuranosy1cytosine) and 4 received cytarabine-based induction chemotherapy. Complete remission (CR) was achieved in 72.2% of the patients after the first induction chemotherapy and 80% of the patients achieved CR after salvage therapy. The overall CR rate was 94% (17/18 patients). These 17 patients underwent hematopoietic stem cell transplantation (9 matched unrelated donors, 5 matched related donors, and 3 haploidentical donors). Relapse occurred in 22% of the patients. Event free survival and overall survival rates were 53.8±12.1% and 53.6±12.1%, respectively, and they were not significantly different according to the type of induction chemotherapy (P=0.690) or the type of donor (P=0.102).
Conclusion
This study outlines the outcomes of pediatric AML patients with FLT3-ITD-mutations in one institution over a decade. Outcomes were significantly improved in this study compared to our previous report in 2004, where RFS and EFS were 0%. This study can provide baseline data for pediatric patients in the pre-FLT3 inhibitor era.

Keywords FLT3-ITD, Acute myeloid leukemia, Pediatric, Overall survival

Article

Original Article

Blood Res 2020; 55(4): 217-224

Published online December 31, 2020 https://doi.org/10.5045/br.2020.2020127

Outcomes of pediatric acute myeloid leukemia patients with FLT3-ITD mutations in the pre-FLT3 inhibitor era

Sujin Choi¹, Bo Kyung Kim^1,2, Hong Yul Ahn^1,2, Kyung Taek Hong^1,2, Jung Yoon Choi^1,2, Hee Young Shin^1,2, Hyoung Jin Kang^1,2,3

Correspondence to:Hyoung Jin Kang, M.D., Ph.D.
Department of Pediatrics, Seoul National University Children’s Hospital, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
E-mail: kanghj@snu.ac.kr

Received: June 4, 2020; Revised: September 29, 2020; Accepted: October 16, 2020

Abstract

Keywords: FLT3-ITD, Acute myeloid leukemia, Pediatric, Overall survival

Abstract

Fig 1.

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Figure 1.Treatment and outcome of patients. ^a)Enocitabine, idarubicin, intrathecal cytarabine; ^b)cytarabine, idarubicin, mitoxantrone.Abbreviations: AML, acute myeloid leukemia; CR, complete remission; DOD, died of disease; HSCT, hematopoietic stem cell transplant; MRD, matched related donor; MUD, matched unrelated donor; N, number; NED, no evidence of disease; TRM, treatment-related mortality.

Blood Research 2020; 55: 217-224https://doi.org/10.5045/br.2020.2020127

Fig 2.

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Figure 2.Patients’ overall survival (OS) and event free survival (EFS).
Abbreviations: Haplo, haploidentical; HSCT, hematopoietic stem cell transplant; MRD, matched related donor; MUD, matched unrelated donor.

Blood Research 2020; 55: 217-224https://doi.org/10.5045/br.2020.2020127

Table 1 . Characteristics of patients with FLT3 mutations..

N	18
Median age at diagnosis	13 (6–19)
Gender (N) F:M	11:7
Prognostic factors (%)
Primary refractory	5 (27.8)
High WBC counta)	4 (22.2)
Secondary AML	2 (11.1)
FAB (N, %)
M1	7 (38.9)
M2	4 (22.2)
M4	6 (33.3)
M5	1 (5.5)
Cytogenetic/molecular (N, %)
Normal	9 (50)
inv (16)	0
KMT2A/MLL	1 (5.5)
PML/RARA	0
AML1/ETO	3 (16.7)
FLT/TKD	1 (5.5)
Induction chemotherapy (N, %)
BH-AC-basedb)	14 (77.7)
Cytarabine-basedc)	4 (22.2)
HSCT (N, %)	17 (94.4)
MUD	9 (52.9)
MRD	5 (27.8)
Haploidentical	3 (16.7)

^a)WBC count of >100×10⁹/L at diagnosis; ^b)enocitabine, idarubicin, intrathecal cytarabine; ^c)cytarabine, idarubicin, mitoxantrone..

Abbreviations: AML, acute myeloid leukemia; CR, complete remission; DOD, died of disease; FAB, French-American-British classification; HSCT, hematopoietic stem cell transplant; MRD, matched related donor; MUD, matched unrelated donor; N, number; TRM, treatment-related mortality..

Table 2 . Characteristics and outcome of study patients (N=18)..

Pt. No.	Sex	Age (yr)	FAB	Cytogenetics at diagnosis	Combined molecularabnormalitya)	Induction	CRd)	HSCT donor type (HLA)	Dx to HSCT(M)	CR to HSCT(M)	Conditio-ning regimen	Engraft-ment (D)	HSCT Compli-cation	OS (entry to death, M)	Relapse (RFS, M)e)	HSCT to last follow up (M)	Outco-me
1	F	19	M4	46, XX		BH-ACb)	Yes	MUD(10/10)	7	5	TBIAcFluda	16	-	16	Yes (4)	9	DOD
2	M	11	M2	46,XY,t(5;21;8) (q13;q22;q22)/46,XY	AML1/ETO	BH-AC	Yes	MUD(9/10)	4	3	TBIAcFluda	14	skin aGVHDlung cGVHD	21	No	16	TRM
3	F	9	M2	49,XX,+8,+11,+18/46,XX		BH-AC	Yes	MUD(10/10)	7	6	TBIAcFluda	14	VOD, liver cGVHD	19	No	11	TRM
4	F	16	M4	46, XX		BH-AC	Yes	MUD(10/10)	7	6	TBIAcFluda	19	lung cGVHD	157	No	150	Alive
5	F	14	M4	46,XX,t(6;9)(p23;q34)46,XX,inv(1)(p13q21),t(6;9)(p23;q34)	DEK/NUP214	BH-AC	Yes	MUD(9/10)	5	4	TBIAcFluda	19	-	130	No	124	Alive
6	F	7	M5	46, XX		BH-AC	Yes	MUD(9/10)	3	2	BuFluVPATG	17	lung cGVHD	108	No	104	Alive
7	M	9	M1	46, XY		BH-AC	Yes	MRD	6	4	TBIAcFluda	12	-	13	Yes (4)	6	DOD
8	M	12	M1	46, XY		BH-AC	Yes	MRD	4	3	BuFluVPATG	11	VOD	106	No	102	Alive
9	F	10	M1	46,XX,t(7;11) (p15;p15)		BH-AC	Yes	MRD	4	3	BuFluVPATG	11	-	36	Yes (28)	32	TRM
10	F	15	M2	46,XX,t(8;21) (q22;q22)	AML1/ETO	BH-AC	Yes	MUD(10/10)	5	4	BuFluVPATG	11	-	106	No	100	Alive
11	M	18	M1	46,XY,t(6;9)(p23;q34)/46,XY	DEK/NUP214	BH-AC	Yes	MRD	5	4	BuFluVPATG	10	VOD, liver cGVHD	7	No	2	TRM
12	F	11	M1	46 XY		BH-AC	Yes	MRD	4	2	BuFluVPATG	10	VOD	32	Yes (12)	27	DOD
13	M	6	M4	46, XY	FLT3/TKD	BH-AC	Yes	MUD(10/10)	4	3	BuFluVPATG	11	VOD,lung cGVHD	101	No	96	Alive
14	F	13	M1	46,XX,16qh+		BH-AC	Yes	MUD(10/10)	4	1	BuFluVPATG	13	skin aGVHD	50	No	46	Alive
15	M	16	M2	45,X,-Y,t(8;21)(q22;q22)	AML1/ETO	Cytarabinec)	Yes	Haplo-identical	7	5	BuFluCy	20	-	73	No	66	Alive
16	F	13	M4	46,XX,t(11;19) (q23;p13.3)	MLL	Cytarabine	Yes	Haplo-identical	5	3	BuFluCy	18	-	70	No	65	Alive
17	M	16	M4	46, XY		Cytarabine	No	(-)	-	-	(-)	-	-	6	No	-	DOD
18	F	14	M1	46, XX	NPM1	Cytarabine	Yes	Haplo-identical	4	3	BuFluCy	16	-	13	No	9	Alive

^a)All patients were tested for FLT3/TKD, CBFB inv(16), AML1/ETO, MLL, and PML/RARA rearrangements at diagnosis. Other molecular abnormalities were tested in some patients only ^b)enocitabine, idarubicin, intrathecal cytarabine; ^c)cytarabine, idarubicin, mitoxantrone; ^d)CR including primary CR and CR after salvage therapies; ^e)months from end of therapy to relapse..

Abbreviations: aGVHD, acute graft versus host disease; BuFluCy, busulfan, fludarabine, cyclophosphamide; BuFluVPATG, Busulfan, etoposide, thymoglobulin, fludarabine; cGVHD, chronic graft versus host disease; CR, complete remission; DOD, died of disease; Dx, diagnosis; FAB, French–American–British classification; HSCT, hematopoietic stem cell transplant; MRD, matched related donor; MUD, matched unrelated donor; TBIAcFluda, TBI, AraC, thymoglobulin, fludarabine; TRM, treatment related mortality; VOD, veno-occlusive disease..