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Case Report
Diagnosis and Treatment of Pediatric Acute Megakaryoblastic Leukemia with NUP98::KDM5A Rearrangement: Case Report
Clin Pediatr Hematol Oncol 2024;31:56-9.
Published online October 31, 2024
© 2024 Korean Society of Pediatric Hematology-Oncology

Hyemin Kang1, Suejung Jo1, Jae Won Yoo1, Seongkoo Kim1, Jae Wook Lee1, Nack-Gyun Chung1, Bin Cho1, Chae Yeon Lee2 and Myungshin Kim2

Departments of 1Pediatrics and 2Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
Correspondence to: Jae Wook Lee
Department of Pediatrics, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea
Tel: +82-2-2258-6192
Fax: +82-2-537-4544
E-mail: dashwood@catholic.ac.kr
ORCID ID: orcid.org/0000-0002-0735-0287
Received September 2, 2024; Revised October 3, 2024; Accepted October 3, 2024.
Abstract
Non-Down syndrome pediatric acute megakaryoblastic leukemia (AMKL) may be classified according to the presence of recurrent genetic abnormalities with prognostic relevance. In this case study, we report on a girl with AMKL, 32 months old at the time of diagnosis, in whom we confirmed the presence of the cryptic, poor prognosis NUP98::KDM5A fusion. The patient achieved complete remission (CR) with the first course of chemotherapy, underwent haploidentical family donor hematopoietic stem cell transplantation (HSCT) without event, but relapsed 5 months after HSCT. Through this case report, we emphasize the good initial response to chemotherapy, and the early relapse despite undergoing HSCT in first CR. We review the limited literature on NUP98::KDM5A (+) pediatric AML, and underscore the need for further study to improve the outcome of patients with this rare AML subtype.
Keywords: NUP98::KDM5A fusion, Acute megakaryoblastic leukemia, Acute myeloid leukemia
Introduction

The overall prognosis of non-Down syndrome pediatric acute megakaryoblastic leukemia (AMKL) is poor, although recent studies show heterogeneity in outcome depending on the defining genetic abnormality [1,2]. Some of these genetic aberrations are cryptic, and require fusion-specific reverse transcription polymerase chain reaction or whole transcriptome sequencing (WTS) for diagnosis [3]. NUP98::KDM5A, resulting from the fusion of nucleoporin 98 (NUP98) on chromosome 11p15 with KDM5A on 12p13 is a recurrent genetic abnormality within pediatric AMKL, with a reported incidence of 9-11.5% in this group of patients [2,4,5]. Although an initial study did not find a worse outcome in NUP98::KDM5A (+) AMKL patients compared with those who were NUP98::KDM5A (−) [4], a subsequent study showed that the presence of NUP98::KDM5A is an independent risk factor for lower overall survival (OS) and greater risk of relapse [6]. However, due to the small number of patients with this fusion, further study is necessary to clarify the prognosis of this genetic subgroup and potential methods of improving therapy for pediatric AMKL patients harboring this genetic abnormality.

In this case report, we give an in-depth account of the diagnosis and treatment of a NUP98::KDM5A (+) AMKL patient. The detailed clinical characteristics that we provide may emerge as common features of this AMKL subtype, pending a broader evaluation of a larger number of patients.

Case Report

A 28–month-old girl first presented with easy bruising. The complete blood count (CBC) at the time showed white blood cell (WBC) count 6.65×109/L, hemoglobin 11.6 g/dL and platelet count of 16×109/L. Under the impression of immune thrombocytopenia, the patient was treated with intravenous immunoglobulin and predni-so-lone, but the thrombocytopenia persisted. Bone marrow (BM) examination done 2 months after the start of prednisolone showed 15% blasts, increasing to 24% blasts in a second BM study done with short-term follow-up. The CBC at the time of the second BM exam showed WBC 9.34×109/L, hemoglobin 10.0 g/dL and platelet 28×109/L, with no peripheral blasts. The BM blasts were positive for CD41a, CD33, CD38, CD4 and HLA-DR in immuno-phenotyping, while chromosome study showed a complex karyotype. Analysis of BM WTS data with the fusion detection tool Arriba [7] confirmed the presence of NUP98::KDM5A fusion (Fig. 1), resulting in the final diagnosis of NUP98::KDM5A (+) AMKL, 4 months after initial presentation with thrombocytopenia. Additional targeted next-generation sequencing (NGS) done on BM showed a pathogenic KRAS mutation, and whole body magnetic resonance imaging did not reveal extramedullary infiltra-tions.

Figure 1. Detection of NUP98::KDM5A using Arriba fusion detection tool (https://arriba.readthedocs.io/en/latest/).

The patient underwent remission induction chemotherapy with the combination of cytarabine 200 mg/m2/day for 7 days and daunorubicin 45 mg/m2/day for 3 days and 1 dose of intrathecal cytarabine. A follow-up BM study showed complete remission (CR), and the patient subsequently underwent second induction with high dose cytarabine and mitoxantrone, and consolidation with cytarabine and idarubicin. BM study done after second induction continued to show CR with minimal residual disease (MRD) negative status according to flow cytometry. Infectious toxicities were limited to one episode of Streptococcus sanguinis bacteremia during the three chemotherapy courses.

Due to the presence of a complex karyotype which designates a patient as high risk according to our acute myeloid leukemia (AML) treatment protocol, and the detection of the NUP98::KDM5A by WTS analysis which has been associated with an overall poor outcome [2,6], the patient proceeded to haploidentical family donor hematopoietic stem cell transplantation (haplo-HSCT) with the patient’s mother as the donor, due to the lack of a human leukocyte antigen-matched donor. BM study prior to HSCT continued to show MRD (−) status. The myeloablative conditioning regimen consisted of fractionated total body irradiation (TBI) totaling 800 cGy (day -8-day -7), busulfan 130 mg/m2/day (day -6-day -5), and fludarabine 40 mg/m2/day (day -6-day -3), as reported previously [8]. Graft-versus-host disease (GVHD) prophylaxis consisted of post-transplantation cyclophosphamide 50 mg/kg/day (day 3-day 4), and cyclosporine starting on day 5. Neutrophil and platelet engraftment occurred at days 15 and 33 respectively, and the patient did not experience acute GVHD, veno-occlusive disease or cytomegalovirus infection. Evaluation at 1 month post-transplant continued to show flow cytometry MRD (−) CR with complete donor chimerism. Due to falling platelet counts, the patient underwent BM study 5 months post-HSCT, which showed 10% blasts, consistent with relapse. The patient received reinduction chemotherapy with fludarabine, cytarabine, idarubicin and granulocyte colony-stimulating factor, with follow-up evaluation and subsequent second allogeneic HSCT planned after CBC recovery.

Discussion

Relevant findings from our patient include a young age at diagnosis of 32 months, the achievement of CR after the first course of remission induction chemotherapy despite the presence of a known poor prognosis NUP98 rearrangement, and the lack of correlation between negative MRD status prior to HSCT and the outcome after HSCT. These features are in agreement with those that were found in a multi-national study of 47 patients with NUP98::KDM5A fusion [6]. In contrast, although the study reported a low incidence of cooperating mutations such as those in RAS and FLT3, possibly indicating that the fusion alone is sufficient for leukemogenesis, we detected a pathogenic KRAS mutation through targeted NGS in our patient. The study also found similarly low event-free survival and OS for NUP98::KDM5A (+) patients, suggesting poor outcome of salvage treatment once relapse occurs. Our case patient has completed reinduction chemotherapy, and the overall outcome of this therapy as well as future planned therapy remains un-known. Overall, the number of reported NUP98::KDM5A (+) AML patients is low, and evaluation of a greater number of patients is necessary to determine important characteristics of this AML subtype.

The optimum method of treating NUP98::KDM5A (+) AML remains unclear. In the large scale multi-national study, only seven of 47 patients (14.9%) received HSCT in first CR. Of these seven patients, five relapsed and four patients died. Nevertheless, the study concludes that NUP98::KDM5A (+) AML patients should be designated as high risk, with consideration of HSCT in first CR [6].

An in-depth understanding of NUP98::KDM5A (+) AML pathogenesis may allow for improved treatment of this high risk AML subtype. Gene expression analysis has shown that NUP98::KDM5A (+) AML cases cluster separately from of NUP98::NSD1 (+) AML, another recurrent NUP98 fusion subtype, with upregulation of HOXB genes, as well as MECOM and PRDM16 [6,9]. Another study report-ed that the chimeric protein produced by NUP98::KDM5A fusion promotes DNA damage through abnormal mitotic progression, resulting in genomic instability and malignant transformation [10]. In terms of therapy, high-throughput screening of potential drugs on NUP98::KDM5A (+) primary patient samples showed in vitro efficacy of vincristine, the PI3K inhibitor omipalisib, and the MEK inhibitor trametinib, although these data require in vivo validation [6]. Another study showed that NUP98-rear-ranged AML is also dependent on Mixed lineage leukemia 1 (MLL1) for leukemogenesis and blockade of the menin-MLL1 interaction decreased leukemia growth in both in vitro and in vivo NUP98::KDM5A leukemia models [11].

With the emerging role of NUP98 fusion (+) AML as a unique disease subtype, these genetic abnormalities have also been reported among South Korean patients, including NUP98::DDX10 and NUP98::NSD1 among pediatric AML patients [12,13]. A recent study reported ten NUP98 fusion (+) cases in a cohort of adult AML patients, with an overall incidence of 5% [14]. None of the ten patients, however, had the NUP98::KDM5A fusion, indicating the possibility that this genetic subtype is rare in older AML patients.

Finally, although the initial report of NUP98::KDM5A fusion was in AMKL [15], as in our case patient, and the fusion remains an important genetic subtype within AMKL, the NUP98::KDM5A fusion has also been reported in all French-American-British (FAB) types of AML, with greater incidence in FAB M7, M5 and M6 [6]. Hence, monitoring for this fusion within pediatric AML overall, may give a more precise estimate of the incidence of this genetic abnormality.

In summary, we describe in detail the diagnosis and treatment of a pediatric AMKL patient with NUP98::KDM5A fusion. The patient was 32 months at diagnosis and harbored a complex karyotype. She achieved CR after the first course of remission induction chemotherapy, but relapsed 5 months after undergoing myeloablative haplo-HSCT in MRD (−) first CR. Although major clinical findings from this patient correlate well with past reports, more study is necessary due to the rarity of this AML subtype. Accurate understanding of its underlying biology may also allow improvement in patient outcome.

Conflict of Interest Statement

The authors have no conflict of interest to declare.

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  • Jae Wook Lee