Minimal residual disease monitoring and preemptive immunotherapies for frequent 11q23 rearranged acute leukemia after allogeneic hematopoietic stem cell transplantation

doi:10.1007/s00277-021-04488-x

. 2021 May;100(5):1267-1281.

doi: 10.1007/s00277-021-04488-x. Epub 2021 Mar 13.

Minimal residual disease monitoring and preemptive immunotherapies for frequent 11q23 rearranged acute leukemia after allogeneic hematopoietic stem cell transplantation

Jing Liu¹, Xiao-Hui Zhang¹, Lan-Ping Xu¹, Yu Wang¹, Chen-Hua Yan¹, Huan Chen¹, Yu-Hong Chen¹, Wei Han¹, Feng-Rong Wang¹, Jing-Zhi Wang¹, Yi-Fei Cheng¹, Ya-Zhen Qin¹, Kai-Yan Liu¹, Xiao-Jun Huang^{1

2

3

4}, Xiao-Su Zhao^{5

6}, Xiao-Dong Mo^{7

8}

Affiliations

¹ National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People's Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, China.
² Peking-Tsinghua Center for Life Sciences, Beijing, 100044, China.
³ Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences, 2019RU029, Beijing, China.
⁴ Collaborative Innovation Center of Hematology, Peking University, Beijing, China.
⁵ National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People's Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, China. zhao.xiaosu@outlook.com.
⁶ Collaborative Innovation Center of Hematology, Peking University, Beijing, China. zhao.xiaosu@outlook.com.
⁷ National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People's Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, China. mxd453@163.com.
⁸ Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences, 2019RU029, Beijing, China. mxd453@163.com.

PMID: 33712867
DOI: 10.1007/s00277-021-04488-x

Minimal residual disease monitoring and preemptive immunotherapies for frequent 11q23 rearranged acute leukemia after allogeneic hematopoietic stem cell transplantation

Jing Liu et al. Ann Hematol. 2021 May.

. 2021 May;100(5):1267-1281.

doi: 10.1007/s00277-021-04488-x. Epub 2021 Mar 13.

Authors

Affiliations

¹ National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People's Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, China.
² Peking-Tsinghua Center for Life Sciences, Beijing, 100044, China.
³ Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences, 2019RU029, Beijing, China.
⁴ Collaborative Innovation Center of Hematology, Peking University, Beijing, China.
⁵ National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People's Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, China. zhao.xiaosu@outlook.com.
⁶ Collaborative Innovation Center of Hematology, Peking University, Beijing, China. zhao.xiaosu@outlook.com.
⁷ National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People's Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, China. mxd453@163.com.
⁸ Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences, 2019RU029, Beijing, China. mxd453@163.com.

PMID: 33712867
DOI: 10.1007/s00277-021-04488-x

Abstract

The prognosis of 11q23/KMT2A-rearranged (KMT2A-r) acute leukemia (AL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is poor. Minimal residual disease (MRD) is an important prognostic factor for relapse. Thus, we aimed to identify the evolution of KMT2A before and after allo-HSCT and the efficacy of preemptive immunotherapies for KMT2A-r AL patients receiving allo-HSCT. KMT2A expression was determined through TaqMan-based RQ-PCR technology. Preemptive immunotherapies included interferon-α and donor lymphocyte infusion. We collected 1751 bone marrow samples from 177 consecutive KMT2A-r AL patients. Pre-HSCT KMT2A positivity was correlated with post-HSCT KMT2A positivity (correlation coefficient=0.371, P<0.001). The rates of achieving KMT2A negativity after allo-HSCT were 96.6%, 92.9%, and 68.8% in the pre-HSCT low-level group (>0, <0.1%), intermediate-level group (≥ 0.1%, <1%), and high-level group (≥1%), respectively. The rates of regaining KMT2A positivity after allo-HSCT were 7.7%, 35.7%, 38.5%, and 45.5% for the pre-HSCT KMT2A-negative, low-level, intermediate-level, and high-level groups, respectively (P<0.001). The 4-year cumulative incidence of relapse after allo-HSCT was as high as 53.7% in the pre-HSCT KMT2A expression ≥ 0.1% group, which was compared to the KMT2A-negative group (15.1%) and KMT2A <0.1% group (31.2%). The clinical outcomes of patients with post-HSCT KMT2A positivity were poorer than those of patients with persistent KMT2A negativity. Although post-HSCT preemptive immunotherapies might help to achieve KMT2A negativity, the long-term efficacy was unsatisfactory. Thus, pre-HSCT KMT2A positivity was significantly associated with post-HSCT KMT2A positivity. The clinical outcomes of patients with post-HSCT KMT2A positivity were poor, which might not be overcome by commonly used immunotherapies.

Keywords: Acute leukemia; Donor lymphocyte infusion; Interferon; KMT2A; Minimal residual disease.

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Cited by

[Progress of allogeneic hematopoietic stem cell transplantation in KMT2A-rearranged acute leukemia].
Liu J, Huang XJ. Liu J, et al. Zhonghua Xue Ye Xue Za Zhi. 2024 May 14;45(5):514-520. doi: 10.3760/cma.j.cn121090-20231026-00230. Zhonghua Xue Ye Xue Za Zhi. 2024. PMID: 38964931 Free PMC article. Review. Chinese.
Single-cell immune landscape of measurable residual disease in acute myeloid leukemia.
Mo X, Zhang W, Fu G, Chang Y, Zhang X, Xu L, Wang Y, Yan C, Shen M, Wei Q, Yan C, Huang X. Mo X, et al. Sci China Life Sci. 2024 Nov;67(11):2309-2322. doi: 10.1007/s11427-024-2666-8. Epub 2024 Jul 19. Sci China Life Sci. 2024. PMID: 39034351
Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients With Acute Myeloid Leukemia Harboring KMT2A Rearrangement and Its Prognostic Factors.
Jiang B, Zhao Y, Luo Y, Yu J, Chen Y, Ye B, Fu H, Lai X, Liu L, Ye Y, Zheng W, Sun J, He J, Zhao Y, Wei G, Cai Z, Huang H, Shi J. Jiang B, et al. Cell Transplant. 2024 Jan-Dec;33:9636897231225821. doi: 10.1177/09636897231225821. Cell Transplant. 2024. PMID: 38270130 Free PMC article.
Outcomes of acute myeloid leukemia with KMT2A (MLL) rearrangement: a multicenter study of TROPHY group.
Zhang R, Huang H, Zhang Y, Xia Y, Huang J, Jiang C, Wang L, Lu H, Pan Z, Wang G, Yang Y, Ma Y, Mo X, Shi W, Hu X, Cao Y. Zhang R, et al. Blood Cancer J. 2025 May 2;15(1):84. doi: 10.1038/s41408-025-01293-x. Blood Cancer J. 2025. PMID: 40316511 Free PMC article.
[Chinese expert consensus of the allogeneic hematopoietic stem cell transplantation for pediatric acute myeloid leukemia (not APL) (2022)].
Stem Cell Application Group, Chinese Society of Hematology, Chinese Medical Association; Chinese Pediatric Society, Chinese Medical Association. Stem Cell Application Group, Chinese Society of Hematology, Chinese Medical Association, et al. Zhonghua Xue Ye Xue Za Zhi. 2022 Oct 14;43(10):802-809. doi: 10.3760/cma.j.issn.0253-2727.2022.10.002. Zhonghua Xue Ye Xue Za Zhi. 2022. PMID: 36709193 Free PMC article. Chinese. No abstract available.

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References

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1. Mancini M, Scappaticci D, Cimino G, Nanni M, Derme V, Elia L, Tafuri A, Vignetti M, Vitale A, Cuneo A, Castoldi G, Saglio G, Pane F, Mecucci C, Camera A, Specchia G, Tedeschi A, Di Raimondo F, Fioritoni G, Fabbiano F, Marmont F, Ferrara F, Cascavilla N, Todeschini G, Nobile F, Kropp MG, Leoni P, Tabilio A, Luppi M, Annino L, Mandelli F, Foa R (2005) A comprehensive genetic classification of adult acute lymphoblastic leukemia (ALL): analysis of the GIMEMA 0496 protocol. Blood 105(9):3434–3441. https://doi.org/10.1182/blood-2004-07-2922 - DOI - PubMed

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[1] Schoch C, Schnittger S, Klaus M, Kern W, Hiddemann W, Haferlach T (2003) AML with 11q23/MLL abnormalities as defined by the WHO classification: incidence, partner chromosomes, FAB subtype, age distribution, and prognostic impact in an unselected series of 1897 cytogenetically analyzed AML cases. Blood 102(7):2395–2402. https://doi.org/10.1182/blood-2003-02-0434 - DOI - PubMed

[2] Schoch C, Schnittger S, Klaus M, Kern W, Hiddemann W, Haferlach T (2003) AML with 11q23/MLL abnormalities as defined by the WHO classification: incidence, partner chromosomes, FAB subtype, age distribution, and prognostic impact in an unselected series of 1897 cytogenetically analyzed AML cases. Blood 102(7):2395–2402. https://doi.org/10.1182/blood-2003-02-0434 - DOI - PubMed

[3] Pui CH, Chessells JM, Camitta B, Baruchel A, Biondi A, Boyett JM, Carroll A, Eden OB, Evans WE, Gadner H, Harbott J, Harms DO, Harrison CJ, Harrison PL, Heerema N, Janka-Schaub G, Kamps W, Masera G, Pullen J, Raimondi SC, Richards S, Riehm H, Sallan S, Sather H, Shuster J, Silverman LB, Valsecchi MG, Vilmer E, Zhou Y, Gaynon PS, Schrappe M (2003) Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements. Leukemia 17(4):700–706. https://doi.org/10.1038/sj.leu.2402883 - DOI - PubMed

[4] Pui CH, Chessells JM, Camitta B, Baruchel A, Biondi A, Boyett JM, Carroll A, Eden OB, Evans WE, Gadner H, Harbott J, Harms DO, Harrison CJ, Harrison PL, Heerema N, Janka-Schaub G, Kamps W, Masera G, Pullen J, Raimondi SC, Richards S, Riehm H, Sallan S, Sather H, Shuster J, Silverman LB, Valsecchi MG, Vilmer E, Zhou Y, Gaynon PS, Schrappe M (2003) Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements. Leukemia 17(4):700–706. https://doi.org/10.1038/sj.leu.2402883 - DOI - PubMed

[5] Meyer C, Burmeister T, Groger D, Tsaur G, Fechina L, Renneville A, Sutton R, Venn NC, Emerenciano M, Pombo-de-Oliveira MS, Barbieri Blunck C, Almeida Lopes B, Zuna J, Trka J, Ballerini P, Lapillonne H, De Braekeleer M, Cazzaniga G, Corral Abascal L, van der Velden VHJ, Delabesse E, Park TS, Oh SH, Silva MLM, Lund-Aho T, Juvonen V, Moore AS, Heidenreich O, Vormoor J, Zerkalenkova E, Olshanskaya Y, Bueno C, Menendez P, Teigler-Schlegel A, Zur Stadt U, Lentes J, Gohring G, Kustanovich A, Aleinikova O, Schafer BW, Kubetzko S, Madsen HO, Gruhn B, Duarte X, Gameiro P, Lippert E, Bidet A, Cayuela JM, Clappier E, Alonso CN, Zwaan CM, van den Heuvel-Eibrink MM, Izraeli S, Trakhtenbrot L, Archer P, Hancock J, Moricke A, Alten J, Schrappe M, Stanulla M, Strehl S, Attarbaschi A, Dworzak M, Haas OA, Panzer-Grumayer R, Sedek L, Szczepanski T, Caye A, Suarez L, Cave H, Marschalek R (2018) The MLL recombinome of acute leukemias in 2017. Leukemia 32:273–284. https://doi.org/10.1038/leu.2017.213 - DOI - PubMed

[6] Meyer C, Burmeister T, Groger D, Tsaur G, Fechina L, Renneville A, Sutton R, Venn NC, Emerenciano M, Pombo-de-Oliveira MS, Barbieri Blunck C, Almeida Lopes B, Zuna J, Trka J, Ballerini P, Lapillonne H, De Braekeleer M, Cazzaniga G, Corral Abascal L, van der Velden VHJ, Delabesse E, Park TS, Oh SH, Silva MLM, Lund-Aho T, Juvonen V, Moore AS, Heidenreich O, Vormoor J, Zerkalenkova E, Olshanskaya Y, Bueno C, Menendez P, Teigler-Schlegel A, Zur Stadt U, Lentes J, Gohring G, Kustanovich A, Aleinikova O, Schafer BW, Kubetzko S, Madsen HO, Gruhn B, Duarte X, Gameiro P, Lippert E, Bidet A, Cayuela JM, Clappier E, Alonso CN, Zwaan CM, van den Heuvel-Eibrink MM, Izraeli S, Trakhtenbrot L, Archer P, Hancock J, Moricke A, Alten J, Schrappe M, Stanulla M, Strehl S, Attarbaschi A, Dworzak M, Haas OA, Panzer-Grumayer R, Sedek L, Szczepanski T, Caye A, Suarez L, Cave H, Marschalek R (2018) The MLL recombinome of acute leukemias in 2017. Leukemia 32:273–284. https://doi.org/10.1038/leu.2017.213 - DOI - PubMed

[7] Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, Dombret H, Ebert BL, Fenaux P, Larson RA, Levine RL, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz M, Sierra J, Tallman MS, Tien HF, Wei AH, Lowenberg B, Bloomfield CD (2017) Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129(4):424–447. https://doi.org/10.1182/blood-2016-08-733196 - DOI - PubMed - PMC

[8] Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, Dombret H, Ebert BL, Fenaux P, Larson RA, Levine RL, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz M, Sierra J, Tallman MS, Tien HF, Wei AH, Lowenberg B, Bloomfield CD (2017) Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129(4):424–447. https://doi.org/10.1182/blood-2016-08-733196 - DOI - PubMed - PMC

[9] Mancini M, Scappaticci D, Cimino G, Nanni M, Derme V, Elia L, Tafuri A, Vignetti M, Vitale A, Cuneo A, Castoldi G, Saglio G, Pane F, Mecucci C, Camera A, Specchia G, Tedeschi A, Di Raimondo F, Fioritoni G, Fabbiano F, Marmont F, Ferrara F, Cascavilla N, Todeschini G, Nobile F, Kropp MG, Leoni P, Tabilio A, Luppi M, Annino L, Mandelli F, Foa R (2005) A comprehensive genetic classification of adult acute lymphoblastic leukemia (ALL): analysis of the GIMEMA 0496 protocol. Blood 105(9):3434–3441. https://doi.org/10.1182/blood-2004-07-2922 - DOI - PubMed

[10] Mancini M, Scappaticci D, Cimino G, Nanni M, Derme V, Elia L, Tafuri A, Vignetti M, Vitale A, Cuneo A, Castoldi G, Saglio G, Pane F, Mecucci C, Camera A, Specchia G, Tedeschi A, Di Raimondo F, Fioritoni G, Fabbiano F, Marmont F, Ferrara F, Cascavilla N, Todeschini G, Nobile F, Kropp MG, Leoni P, Tabilio A, Luppi M, Annino L, Mandelli F, Foa R (2005) A comprehensive genetic classification of adult acute lymphoblastic leukemia (ALL): analysis of the GIMEMA 0496 protocol. Blood 105(9):3434–3441. https://doi.org/10.1182/blood-2004-07-2922 - DOI - PubMed

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Minimal residual disease monitoring and preemptive immunotherapies for frequent 11q23 rearranged acute leukemia after allogeneic hematopoietic stem cell transplantation

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Minimal residual disease monitoring and preemptive immunotherapies for frequent 11q23 rearranged acute leukemia after allogeneic hematopoietic stem cell transplantation

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