High-Risk Acute Myeloid Leukemia Developing in a Patient with Recurrent Melanoma: A Case Report

Abstract

Introduction

Advances in cancer therapeutics have led to an expanding population of cancer survivors, accompanied by an increased recognition of secondary malignancies. A bidirectional relationship between cutaneous melanoma and hematologic malignancies has been described, though acute myeloid leukemia (AML) following melanoma – particularly in the absence of prior chemotherapy or radiation – remains rare.

Case Report

A man in his fifties with no significant comorbidities presented with a chronic pigmented lesion on the lower back, confirmed as superficial spreading melanoma (Breslow thickness 3.3 mm, Stage IIIC). He underwent wide local excision with sentinel lymph node biopsy followed by 1 year of adjuvant BRAF/MEK inhibitor therapy. The patient’s recurrent dermal melanoma was treated with immune checkpoint inhibitors, leading to complete remission. One year after discontinuation of immunotherapy, surveillance imaging revealed recurrent melanoma with concurrent pancytopenia. Bone marrow biopsy established a diagnosis of AML with complex cytogenetics. The patient achieved complete remission following FLAG induction chemotherapy, and concurrent targeted therapy was resumed for melanoma control.

Conclusion

This case illustrates a rare occurrence of AML developing after melanoma in a patient without prior exposure to cytotoxic chemotherapy or radiation. Potential contributing mechanisms include shared oncogenic pathways, ultraviolet-induced genomic instability, and immunotherapy-related clonal hematopoietic expansion. These findings emphasize the necessity for continued investigation into the long-term hematologic consequences of immune checkpoint inhibition and the molecular pathways linking solid tumors to myeloid malignancies.

Introduction

Recent advances in cancer detection and therapeutic strategies have resulted in an expanding population of cancer survivors, bringing increased focus to the risk of developing secondary malignancies. A bidirectional relationship between cutaneous melanoma (CM) and hematologic cancers – particularly lymphoid malignancies – has been well documented [1]. A meta-analysis demonstrated that 62.4% of patients with melanoma subsequently developed hematologic malignancies (HMs), whereas 19.6% of individuals with HMs later developed melanoma [1]. Despite these associations, cases of acute myeloid leukemia (AML) or other myeloid neoplasms occurring after melanoma remain uncommon, particularly in the era of modern, targeted melanoma therapies.

Traditionally, the management of melanoma, akin to many solid tumors, relied on cytotoxic chemotherapy. Despite its limited therapeutic efficacy in melanoma, chemotherapy remained one of the few systemic treatment modalities available for metastatic disease prior to the advent of targeted and immune-based therapies. Historically, the occurrence of secondary HMs in patients with melanoma has been predominantly associated with prior exposure to cytotoxic chemotherapeutic agents or radiotherapy employed in the treatment of advanced or metastatic disease [2, 3].

Over the past decade, targeted therapies – such as BRAF and MEK inhibitors – and immune checkpoint inhibitors have become central components in the management of melanoma. Both therapeutic approaches depend on the integrity and responsiveness of the host immune system [4, 5]. Although immunotherapy has demonstrated substantial efficacy across a spectrum of malignancies,1 including Hodgkin lymphoma, its long-term hematologic consequences – particularly the potential for therapy-related myeloid neoplasms – are not yet fully elucidated. A small number of cases have described the development of myeloid malignancies following immune checkpoint blockade; however, interpretation of these findings is often limited by confounding factors such as prior exposure to cytotoxic chemotherapy or radiation [6]. Furthermore, the influence of a secondary HM on the persistence and durability of immunotherapy-induced remission in metastatic melanoma remains poorly understood.

This case report describes a rare clinical scenario of AML diagnosed concurrently with recurrent metastatic melanoma. It seeks to elucidate potential shared pathogenic mechanisms and examines whether prior immunotherapy may have contributed to leukemogenesis, or conversely, if AML-associated immune dysregulation might have facilitated the resurgence of previously controlled metastatic melanoma.

Case Presentation

A man in his fifties, with no significant medical comorbidities or family history of malignancy, presented with a chronic, evolving pigmented lesion on his lower back. Histopathologic examination of a skin biopsy confirmed a superficial spreading melanoma arising within a pre-existing nevus. He subsequently underwent wide local excision with 2-cm margins and sentinel lymph node biopsy, which demonstrated residual invasive melanoma with a Breslow thickness of 3.3 mm (Clark level IV) and metastatic involvement of both sampled left inguinal lymph nodes. The disease was classified as pT3a N3c (Stage IIIC). Comprehensive staging with brain MRI and PET imaging revealed no evidence of distant metastasis. The patient was initiated on adjuvant targeted therapy with dabrafenib and trametinib (BRAF/MEK inhibitors) for 1 year.

Several months following completion of adjuvant therapy, a new pigmented lesion was identified in the left suprapubic region. Histopathologic evaluation confirmed recurrent metastatic dermal melanoma, although subsequent brain MRI and PET imaging remained negative for distant metastases. The patient was initiated on combination immunotherapy with relatlimab and nivolumab. After five cycles, interval imaging demonstrated apparent pseudo-progression characterized by an enlarged and morphologically abnormal left inguinal lymph node. Fine-needle aspiration confirmed metastatic melanoma. Although lymph node dissection was advised, the patient elected to defer surgical intervention due to his active participation in competitive fitness training. Immunotherapy was continued for approximately 1 year, during which serial imaging and biopsy assessments remained negative for active disease. The patient then discontinued therapy and transitioned to surveillance monitoring.

One year after cessation of immunotherapy, surveillance PET imaging continued to show no evidence of active disease. However, repeat imaging several months after that revealed intra-abdominal recurrence and a new cutaneous lesion on the lower back. Fine-needle aspiration confirmed recurrent melanoma. Concurrently, the patient reported 2 months of fatigue and diffuse bone pain. Laboratory evaluation revealed new-onset pancytopenia (WBC 1.3 × 10⁹/L, ANC 1.0; hemoglobin 11.2 g/dL; platelets 116 × 10⁹/L).

Given the new-onset pancytopenia and clinical features suggestive of a HM, the patient underwent urgent bone marrow aspiration and biopsy, which established a diagnosis of AML (shown in Fig. 1). Cytogenetic evaluation revealed a complex karyotype: 46,XY,del(16)(q12q24) [6]/47,XY,+8 [2]/54,sl2,+2,+5,+6,+12,+14,+15,+20 [1]/46,XY [12]. Fluorescence in situ hybridization demonstrated deletion of chromosome 16q, corresponding to loss of CBFB at 16q22 in 23% of cells. Myeloid next-generation sequencing identified a Tier I NUP98 (exon 12)::NSD1 (exon 6) fusion mutation, consistent with high-risk disease biology.

Fig. 1.

Bone marrow biopsy demonstrating increased myeloid blasts with mildly irregular nuclear contours, fine chromatin, prominent nucleoli, and scant basophilic cytoplasm containing variable eosinophilic granules, consistent with AML.

In view of the complex cytogenetic findings and NUP98 fusion, curative treatment options were deemed limited, and management prioritized remission after induction for disease control and preservation of quality of life. Concurrent imaging identified small hemorrhagic brain metastases, which were treated with stereotactic radiosurgery to permit timely initiation of AML-directed therapy. Following multidisciplinary discussion, the patient underwent FLAG induction chemotherapy (fludarabine, cytarabine, and granulocyte colony-stimulating factor) for 1 week, achieving complete morphologic remission on post-induction bone marrow evaluation performed 3 weeks after therapy. The immediate post-induction course was complicated by neutropenic fever, which required a 5-day course of cefepime with subsequent recovery. Given the persistence of BRAF V600E-mutated melanoma and the limitations of immunotherapy in the context of prolonged cytopenia and immunosuppression, concurrent targeted therapy with dabrafenib and trametinib was re-initiated for melanoma management. The patient reported a high level of satisfaction with the treatment and demonstrated sustained functional preservation. Given his preserved functional status and continued bone marrow remission, the patient was scheduled to undergo FLAG consolidation therapy to reinforce his complete response, along with NM PET melanoma imaging and brain MRI every 3–4 months for ongoing disease surveillance.

Discussion

An expanding body of evidence has highlighted a bidirectional association between CM and HMs, suggesting the existence of shared oncogenic and immunologic mechanisms linking these distinct entities [1]. Ultraviolet radiation (UVR) – a well-established etiologic driver of CM, implicated in up to 70% of cases [7] – has also been associated with an increased incidence of HM [8, 9]. This relationship is thought to arise, at least in part, from UVR-induced immunosuppression and consequent impairment of tumor immune surveillance. Chronic inflammation represents an additional overlapping pathogenic factor. In melanoma, UVR exposure can trigger persistent inflammatory signaling, while pro-inflammatory cytokines such as IL-6 and TNF-α promote malignant cell survival and immune dysregulation in hematologic cancers [10]. In this case, cumulative UVR exposure may have not only initiated melanomagenesis but also contributed to the subsequent development of AML through shared immunologic and inflammatory pathways.

Cancer-associated immunosuppression is a recognized hallmark of both melanoma and AML, with each malignancy capable of subverting immune defenses to facilitate its own progression [1]. Melanoma cells evade immune detection by secreting immunosuppressive cytokines and downregulating the antigen presentation machinery, enabling metastatic dissemination via the lymphatic system [1]. Similarly, AML is characterized by profound myeloid-driven immune dysfunction that impairs both adaptive and innate responses. In this patient, the temporal concurrence of AML onset and melanoma recurrence raises the possibility of a reciprocal immunosuppressive interplay, whereby the immune dysregulation induced by one malignancy may have created a permissive environment for the manifestation or progression of the other.

Oxidative stress further represents a mechanistic bridge between CM and HM [1]. In melanoma, UV-induced reactive oxygen species (ROS) drive melanogenesis and promote genomic instability, including activating mutations in oncogenes such as BRAF [1]. In AML, elevated ROS similarly induces DNA damage, activates oncogenic signaling cascades (e.g., PI3K/Akt, MAPK), and enhances leukemic cell proliferation [10]. Supporting this shared biology, studies have identified overlapping somatic mutations in both malignancies, notably involving NRAS and TP53, underscoring potential common molecular pathways in tumorigenesis [1]. Together, these findings reinforce the notion that melanoma and AML may, in select patients, arise through interconnected pathogenic processes involving cumulative genotoxic stress, immune dysregulation, and oxidative injury.

Therapy-related AML, defined as AML arising secondary to prior cytotoxic, radiation, or immunosuppressive therapy for an unrelated condition, accounts for approximately 7–8% of AML cases [11]. Several non-mutually exclusive mechanisms have been proposed in its pathogenesis, including chromosomal translocations leading to fusion oncogenes, induction of genomic instability, therapy-induced bone marrow inflammation creating a leukemogenic environment, and the selective expansion of pre-existing, treatment-resistant hematopoietic clones [11].

With the evolution of melanoma therapeutics, treatment strategies have increasingly emphasized molecularly targeted agents and immune checkpoint inhibitors. In this case, the patient’s melanoma harbored a BRAF V600E mutation, for which he initially received combination BRAF/MEK inhibition with dabrafenib and trametinib. Current literature does not support a direct causal link between BRAF/MEK inhibitors and the development of AML.

Upon disease progression, the patient was transitioned to dual immune checkpoint blockade with relatlimab and nivolumab. Although immunotherapy has not been definitively implicated in the pathogenesis of AML, isolated reports have described the development of myeloid malignancies following checkpoint inhibitor therapy, most often in patients with prior exposure to cytotoxic chemotherapy or radiation [6]. To date, seven cases have been reported in which patients developed myeloid neoplasms during or shortly after treatment with PD-1/PD-L1 inhibitors, with or without CTLA-4 inhibition, for solid tumors [6, 12, 13]. Notably, one case described the onset of acute myelomonocytic leukemia after only three cycles of pembrolizumab, raising the possibility that PD-1 blockade may have accelerated the progression of previously subclinical disease [12]. In this context, PD-1 inhibition has been hypothesized to promote expansion of pre-existing myeloid clones harboring oncogenic mutations [12]. Emerging data further suggest that prolonged immune checkpoint inhibition may induce or expand clonal hematopoiesis (CH) through therapy-related somatic mutations, potentially increasing the risk of secondary HMs [14]. In one reported case, a patient with advanced lung adenocarcinoma treated with atezolizumab in combination with platinum-based chemotherapy developed autoimmune hemolytic anemia and myelodysplastic syndrome, with subsequent progression to AML 20 months after treatment initiation, highlighting the potential for compounded risk when immunotherapy is combined with cytotoxic agents [13].

Other forms of immunotherapy have also been associated with secondary myeloid neoplasms. Chimeric antigen receptor T-cell (CAR-T) therapy has been associated with the development of AML and myelodysplastic syndrome in approximately 2%–10% of patients within 5 years of infusion [15]. Importantly, however, these patients typically have substantial prior exposure to mutagenic chemotherapy, including chemotherapy regimens administered immediately before CAR-T infusion, which independently increases the risk of therapy-related myeloid malignancies [15]. Studies evaluating CH in CAR-T recipients have demonstrated that many clones are detectable at baseline prior to CAR-T infusion [16, 17]. Among 40 patients with evaluable samples, 46 CH clones were identified before CAR-T therapy compared with 51 clones after infusion [16, 17], rendering it unclear whether CAR-T therapy drives expansion of pre-existing clones or contributes to the emergence of new clonal populations [18].

In the present case, shared biological susceptibilities may have predisposed the patient to AML, while immune checkpoint blockade could have contributed to its clinical manifestation through mechanisms involving clonal expansion or genomic instability. Although the causal relationship remains speculative, this case highlights the importance of vigilant long-term hematologic monitoring in patients receiving extended immunotherapy, particularly those with predisposing molecular or environmental risk factors [19].

Interestingly, immunotherapy itself is being actively investigated as a potential therapeutic strategy for AML. A recent report described a patient with coexistent AML and melanoma who achieved sustained disease stability for over 14 months on pembrolizumab therapy [20]. Additionally, early-phase trials combining immune checkpoint inhibitors with conventional AML regimens have demonstrated encouraging results, though toxicity profiles and long-term safety remain to be fully characterized [19].

This case report highlights a rare presentation of AML arising in close temporal proximity to recurrent metastatic melanoma, particularly in a patient without prior exposure to cytotoxic chemoradiation, thereby adding meaningful clinical and biological context to a limited body of literature. By integrating detailed clinicopathologic findings, it offers insight into potential immunologic and molecular intersections between these malignancies and contributes to emerging hypotheses regarding immune dysregulation, CH, and therapy-related leukemogenesis. The patient’s achievement of AML remission alongside stabilization of melanoma further underscores the feasibility of coordinated cytotoxic and targeted therapy in complex dual-malignancy settings. However, as a single case, it cannot establish causality or generalize the observed association, and the temporal overlap of melanoma recurrence and AML onset limits the ability to determine whether immunotherapy, underlying genomic susceptibility, or environmental exposures most contributed to leukemogenesis. Given these overlapping factors, the precise driver of AML development in this context remains uncertain.

Conclusion

This case presents a rare instance of AML emerging following melanoma in the absence of prior cytotoxic chemotherapy or radiation exposure. Although the precise pathophysiologic mechanism remains uncertain, potential contributing factors include shared oncogenic pathways and immunotherapy-associated genomic perturbations. This observation emphasizes the necessity for continued investigation into the long-term hematologic consequences of immune checkpoint inhibition and the molecular pathways linking solid tumors to myeloid malignancies.

The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000551479).

Statement of Ethics

Research Ethics Board approval is not required for this study in accordance with our local guidelines. The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

Maisha Anika wrote and reviewed the manuscript. Tarek Haykal and Dale Bixby assisted in the direction for writing and reviewed the manuscript.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.