Abstract

Acute myeloid leukemia (AML) with the high-risk variant inv(3)/t(3;3) or t(3;3)(q21;26.2) is rarely seen in the pediatric and young adult population. It is associated with poor outcomes with ineffective therapeutic options. Here, we present a case of an 18-year-old female with treatment refractory inv(3) AML in whom remission was unable to be obtained. Better treatment options are needed given the increased resistance to traditional therapy this subtype portrays. Here, we review the literature on pediatric and young adult inv(3) AML along with newer therapeutic options.

1. Introduction

Acute myeloid leukemia (AML) is more common in the adult population, representing approximately 80% of all adult leukemias compared to 20% of childhood leukemias [1]. Survival rates for pediatric AML have drastically increased over the past few decades with improved supportive care along with more precise risk stratification and associated treatments [2]. However, this is not true for all as certain cytogenetic findings are considered high-risk (HR) given their inferior outcomes and resistance to conventional treatment. One HR AML variant is inv(3)(q21q26.2) or t(3;3)(q21;26.2), accounting for only 1-2% of all AML cases and sparsely seen in the pediatric population [3, 4]. It is classified by the World Health Organization (WHO) as an independent entity of AML and is also a prognostic marker for poor outcomes with resistance to standard chemotherapy [3, 5–7]. Here, we present a case of a young adult diagnosed with treatment refractory inv(3) AML. We also review the relevant literature to bring awareness of this subtype of AML that is rarely seen in the pediatric and young adult population.

2. Case Description

An 18-year-old female presented with prolonged fatigue and easy bruising. Her complete blood count was significant for anemia along with leukocytosis with the presence of peripheral blasts. Bone marrow aspirate demonstrated a hypocellular marrow, including 17% blasts. Flow cytometry was consistent with a myeloid phenotype (CD34+, CD117+). Cytogenetics were significant for inv(3)(q21q26.2);MECOM(EVI1). Next-generation sequencing (NGS) myeloid panel showed variants along with associated allelic frequencies (VAF) in NRAS (VAF 50%), WT1 (VAF 38%), and GATA2 (VAF 47%). No FLT3-TKD mutation was detected, with only weak FLT3-ITD positivity (ITD allelic ). Our patient was diagnosed with HR inv(3) AML.

She received induction therapy per Children’s Oncology Group (COG) protocol AAML1831, arm B, with intravenous (IV) liposomal cytarabine-daunorubicin (CPX-351) and gemtuzumab, on study. No central nervous system disease was present (CNS1). Disease assessment with repeat bone marrow aspirate revealed an increased presence of blasts up to 65% on morphology. She was taken off study and treated with a cycle of IV azacitidine and oral venetoclax (VEN/AZA). Repeat disease assessment showed continued presence of disease with 17% blasts via morphology and 7% via minimal residual disease (MRD). Another cycle of VEN/AZA was given. Repeat disease assessment once again showed persistent disease with 11% blasts via morphology and 3.6% via MRD. Continued salvage therapy was given with IV thiotepa, vinorelbine, topotecan, and clofarabine (TVTC). Disease assessment after this showed 20% blasts via morphology along with 6.3% via MRD.

Our patient overall tolerated these therapies well with minimal complications. Given the significant refractory nature of her disease, we discussed the poor prognosis. Our patient and her family elected to pursue continued therapy and are exploring clinical trial options with hope of ultimately being able to undergo a hematopoietic stem cell transplant (HSCT) for cure.

3. Discussion

Despite advancements in the understanding of AML biology, limited progress has been made in treatment outcomes for patients with HR AML, including inv(3) [1, 2, 4, 6]. This mutation results in a gene inversion which places the ecotropic viral integration site-1 (EVI1) gene, a highly conserved proto-oncogene, next to the ribophorin 1 (RPN1) gene and GATA2 enhancer, causing transcriptional activation of EVI1. This overexpression leads to increased myeloid cell proliferation as well as impaired cellular differentiation [3–5, 8–11]. Increased EVI1 expression in AML patients has been linked to poorer outcomes and treatment refractory disease, with inv(3) demonstrating the highest increases in EVI1 overexpression [12].

The median OS for patients with inv(3) AML is dismal with a large-scale study reporting a median OS of 10 months from diagnosis [5]. The poor prognosis is thought to be contributed by an increased resistance to chemotherapy causing an inability to achieve a complete remission (CR), as well as a high incidence of early relapse in those patients who do achieve this [4, 5, 11]. This variant is more commonly seen in adults and is exceedingly rare in pediatric patients [1, 3, 4]. Within the literature, only four cases of inv(3) AML have been reported in patients aged 0-18 years (Table 1) [11–14]. While the specific treatment and clinical course data are not available for the published cases, the treatment refractory nature of the inv(3) variant was highlighted.

Better treatments are needed for patients with inv(3) AML. Increased overall survival (OS) is seen in patients who are able to achieve a CR and proceed to a HSCT [15]. HSCT in HR AML has been associated with a longer median OS compared to standard chemotherapy alone. However, early relapse after HSCT has been well described in patients with inv(3) AML [4, 5, 10]. This data is confounded by the fact that patients are often transplanted with active disease present as part of their salvage regimen [4]. Given the increased chance for definitive cure with HSCT, efforts should be made to find treatments aimed at achieving a CR to facilitate a HSCT.

Alternative therapies that have been explored include targeting EVI1 transcriptional regulation given the high overexpression present in inv(3) AML. With the use of next-generation sequencing (NGS), additional mutations in RAS/RTK signaling pathways have also been detected alongside inv(3), indicating the possible application of FLT3 or PIK3 inhibition in these patients [4, 9]. One case showed achievement of CR in an adult patient with inv(3) AML following treatment with dasatinib, a tyrosine kinase inhibitor targeting AKT/STAT3, allowing for successful HSCT [14]. Hypomethylating agents (HMAs) such as azacitidine or decitabine have been used for many years in the treatment of AML, including the pediatric population [16, 17]. B cell lymphoma 2 (BCL-2) inhibitors, such as venetoclax, have been combined with HMAs in recent years as they have the potential to increase tumor sensitivity to HMAs, with further large-scale pediatric trials ongoing to assess sustained efficacy [17].

Developing immunotherapies for AML presents significant challenges including limited tumor-specific antigens and myeloid antigen heterogeneity [18, 19]. However, multiple targets have been explored including CD33, CD123, CLL-1, CD70, TIM-3, and folate receptor α and β. Clinical trials are ongoing to explore the efficacy of these modalities with the use of monoclonal and bispecific antibodies, antibody-drug conjugates, and chimeric antigen receptor (CAR) T cells (Table 2) [18, 19]. Additionally, trials are being conducted to combat pitfalls of immunotherapy in AML including minimizing toxicities, increasing efficacy, and overcoming resistance [18].

Pediatric and young adult inv(3) AML is a rare disease with a dismal prognosis. As with our patient, the hope is to achieve a CR and successfully undergo a HSCT for long-term cure, but this is not easily done. Continued research to find better treatment options is needed to better help this population.

Abbreviations

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

Open Access funding was enabled and organized by BTAA 2023.