Salvage With Revumenib: Targeting KMT2A‐Rearranged Isolated Leukemia Cutis Identified in the Extramedullary Disease

ABSTRACT

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy associated with a high risk of relapse. Leukemia cutis is characterized by the presence of neoplastic leukocytes infiltrating the skin. Here, we present a previously treated AML patient who relapsed with isolated leukemia cutis without bone marrow involvement. Fluorescence in situ hybridization (FISH) and RNA sequencing of the skin lesion revealed a KMT2A::MLLT6 rearrangement, which enabled the use of revumenib. This case highlights the diagnostic complexity and therapeutic implications of isolated extramedullary AML relapse and underscores the need to perform genetic testing at the site of disease recurrence—especially without bone marrow involvement of relapsed disease.

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1. Introduction

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that poses a significant risk of recurrence, even after undergoing allogeneic stem cell transplantation. Disease relapse remains the leading cause of poor outcomes after transplantation and has a profound negative impact on survival, with an estimated 2‐year survival rate of less than 20% [1]. In that regard, extramedullary relapses represent a unique diagnostic and therapeutic challenge. Timely diagnosis is critical, as delays in intervention can result in progressive bone marrow involvement. Leukemia cutis is the infiltration of leukemic cells into the skin, acting as a form of extramedullary disease that signifies advanced leukemia, and is often associated with poor prognosis. Here, we present the case of a previously treated patient with AML who relapsed with isolated leukemia cutis without bone marrow involvement 1‐year post‐allogeneic stem cell transplantation.

2. Case Presentation

A 70‐year‐old female was referred for hematologic evaluation following the incidental discovery of circulating blasts during routine blood work. Laboratory findings revealed mild normocytic anemia and thrombocytopenia. A subsequent bone marrow biopsy demonstrated hypercellular marrow (approximately 80%) with extensive blast infiltration, confirming a diagnosis of AML.

G‐banded chromosome analysis of the diagnostic bone marrow sample taken at the end of 2023 identified a complex karyotype with additional copies of chromosomes 2, 6, 8, 19, and 21. Concurrent FISH revealed extra copies of 8q21.3 (RUNX1T1) and 21q22 (RUNX1) regions in 96.6% of cells, reflecting trisomy 8 and 21 seen in chromosome analysis (Figure 1A). Additionally, a translocation—t(11;17)(q23;q21), involving Chromosomes 11 and 17, was identified, which was confirmed by KMT2A rearrangement, previously known as mixed‐lineage leukemia (MLL) rearrangement (11q23), and detected in 95.3% of cells by FISH analysis (Figure 1A–C). For molecular profiling of the diagnostic bone marrow aspirate biopsy, a next‐generation sequencing (NGS) gene panel was performed. The results of DNA target revealed c.3010C>T; p.Gln1004* variant in the BCOR gene (NM_001123385.1), and c.183A>T; p.Gln61His variant in the NRAS gene (NM_002524.4). RNA sequencing NGS panel was not performed on the diagnostic bone marrow sample.

FIGURE 1.

Cytogenetic analysis of diagnostic bone marrow specimen. (A) All 20 cells in metaphase analyzed from unstimulated bone marrow cultures showed a complex hyperdiploid karyotype with t(11;17) translocation. (B) Ideogram representation of breakpoints of t(11;17) translocation, resulting in the KMT2A::MLLT6 in 5′‐3′ orientation on derivative Chromosome 11. (C) Concurrent FISH analysis showed KMT2A rearrangement, and four copies of RUNX1 on Chromosome 21 and three copies of RUNX1T1 on Chromosome 8, consistent with G‐banded chromosome analysis.

The patient underwent induction chemotherapy with liposomal daunorubicin and cytarabine (Ara‐C), achieving complete remission. Due to a decline in cardiac ejection fraction, consolidation therapy was modified to include high‐dose Ara‐C.

Following four cycles of consolidative Ara‐C, the patient received an allogeneic peripheral blood stem cell transplant from a matched unrelated donor using reduced‐intensity conditioning with fludarabine and busulfan, with thymoglobulin as part of graft‐versus‐host prophylaxis. Posttransplant, her course was complicated by Grade 2 cutaneous graft‐versus‐host disease, which responded to systemic corticosteroids.

Around day 150 posttransplant, maintenance therapy with oral azacitidine and venetoclax was initiated. One year after transplantation, the patient developed a new erythematous papule on the right antecubital fossa (Figure 2A). Immunohistochemical studies on the right antecubital lesion skin biopsy, which was collected in mid‐2025, demonstrated CD45 positive, CD4 positive, and CD117 negative stains and confirmed leukemia cutis consistent with disease relapse (Figure 2B). A concurrent bone marrow biopsy, however, showed no evidence of disease relapse. FISH analysis was negative, and cytogenetics revealed a normal female karyotype, and NGS of the bone marrow was unremarkable. However, molecular profiling of skin biopsy of right antecubital lesion, a comprehensive NGS panel that targets both DNA and RNA to analyze small variants, copy number variations, gene fusions, and splicing variants. This test is used to identify clinically significant genetic variants in a patient's tumor that may have therapeutic, prognostic, or diagnostic implications. The results of DNA target revealed c.3010C>T; p.Gln1004* variant in the BCOR gene (NM_001123385.1), and c.183A>T; p.Gln61His variant in the NRAS gene (NM_002524.4). Notably, the results of RNA targets revealed one Tier 1 KMT2A::MLLT6 translocation (Table S1) as previously identified in the diagnostic bone marrow sample in cytogenetics testing, significantly altering the patient's therapeutic options. This molecular discovery enabled the initiation of revumenib, a recently approved menin inhibitor specifically developed for relapsed or refractory AML with KMT2A rearrangements. Following initiation of revumenib at a dose of 160 mg twice a day, the patient has remained in remission, confirmed by PET CT and bone marrow biopsy and aspirate, up to the time of this report, now 6 months from the start of treatment.

FIGURE 2.

Clinical presentation, immunohistochemical studies, cytogenetic, and molecular analysis of right antecubital lesion skin biopsy. (A) Clinical presentation of right antecubital lesion. (B) Immunohistochemical studies of skin lesion showed CD45‐ and CD4‐positive and CD117‐negative stain results. (C) FISH analysis on FFPE skin lesion tissue showed four copies of RUNX1 on Chromosome 21 and three copies of RUNX1T1 on chromosome and (D) KMT2A rearrangement. (E) Breakpoints of KMT2A::MLLT6 fusion gene identified in next‐generation sequencing analysis of FFPE skin lesion tissue.

3. Discussion

Extramedullary disease is identified in approximately 10%–15% of newly diagnosed AML cases, though overt skin involvement—leukemia cutis—is less common, occurring in only about 3%–5% of patients [2]. Extramedullary disease has been frequently observed and specifically targeted in clinical trials for menin inhibitors like revumenib, bleximenib, and ziftomenib. Clinical trials and reports indicate that these drugs yield significant responses in both bone marrow and extramedullary leukemia sites [3]. Despite the fact that allogeneic stem cell transplantation has significantly improved survival of this disease, posttransplant relapse remains a challenge and a major contributor to poor outcomes of this disease [1]. While most relapses occur in the bone marrow, isolated extramedullary relapse (iEMR) is relatively uncommon after stem cell transplantation. In a cohort of 257 AML patients who underwent allogeneic hematopoietic cell transplantation, the 5‐year cumulative incidence of isolated iEMR was 9% [4]. Whereas another retrospective study of 316 transplanted patients with underlying AML, acute lymphoid leukemia, and chronic myeloid leukemia (CML), reported iEMR in 4.1% of cases. Among the 13 patients with iEMR, seven had AML. The central nervous system was the most frequently involved site, while isolated leukemia cutis was reported in only one case [5].

Poor outcomes are thought to result from resistance of extramedullary sites to graft‐versus‐leukemia (GVL) effects. Although chronic graft‐versus‐host disease is typically associated with protection against systemic relapse, this protective effect does not extend to extramedullary relapse [6, 7]. This observation suggests that the GVL activity may be less effective in peripheral tissues than in the bone marrow. In addition, immune escape mechanisms such as human leukocyte antigen (HLA) loss and clonal evolution may preferentially promote extramedullary disease. Historically, these relapses have shown better responses to cytotoxic chemotherapy than to donor lymphocyte infusion (DLI). Several studies have also identified risk factors for extramedullary relapse after allogeneic hematopoietic cell transplantation in AML, including prior extramedullary involvement, high‐risk cytogenetic features, and disease status at the time of transplantation [4].

In our patient, despite the absence of extramedullary involvement at any site prior to transplantation, multiple high‐risk cytogenetic and molecular features were present at diagnosis, such as complex structural and numerical abnormalities and 11q23 (KMT2A) rearrangement. Taken together, these abnormalities may have contributed to her increased susceptibility to developing extramedullary relapse.

Treatment of relapsed extramedullary relapse in AML remains challenging, particularly following allogeneic transplantation, where therapeutic options are limited, and outcomes are poor. Available approaches include salvage cytotoxic chemotherapy, localized radiation therapy, DLI, or a second stem cell transplant; however, all are generally associated with unfavorable outcomes [8].

Perhaps the most clinically significant aspect of this case is the therapeutic implication of detecting a KMT2A::MLLT6 rearrangement within the skin lesion. With the recent development of menin inhibitors, the treatment landscape for AML harboring KMT2A rearrangements has evolved considerably, underscoring the importance of accurate molecular identification in extramedullary sites. Revumenib disrupts the interaction between menin and KMT2A‐fusion proteins, thereby downregulating oncogenic transcription programs (e.g., HOXA, MEIS1) that sustain leukemic proliferation. The US Food and Drug Administration (FDA) approved revumenib for patients with relapsed or refractory AML in November 2024 based on positive results from the AUGMENT‐101 trial [9].

Furthermore, our patient's clinical presentation of extramedullary relapse as a single cutaneous papule emphasizes the importance of taking every new clinical finding seriously in posttransplant patients, even those that appear minor or isolated, as they may represent the earliest sign of disease recurrence. Most iEMRs eventually progress to bone marrow involvement, with subsequent systemic relapse occurring in approximately 50% of cases. Our case also highlights the importance of performing comprehensive molecular profiling of tissue from extramedullary sites, particularly in iEMR cases, as bone marrow studies show no concurrent evidence of relapse and are historically convenient for molecular testing. Such testing can uncover actionable mutations, guide therapeutic decision‐making, and potentially expand treatment options.

4. Conclusion

This case of isolated leukemia cutis without morphologic, cytogenetic, or molecular evidence of marrow relapse reminds us that relying only on bone marrow testing may overlook actionable findings. Molecular profiling of the cutaneous lesion revealed a KMT2A::MLLT6 rearrangement, enabling use of the menin inhibitor revumenib. The patient's sustained remission with this targeted therapy highlights the importance of identifying actionable mutations in extramedullary sites, especially as precision therapeutics transform the management of molecularly distinct AML subsets.

Author Contributions

B.A. and T.I.S. designed the study and wrote the manuscript. X.W. performed immunohistochemical studies. T.I.S., L.J., and M.A. performed FISH and chromosome karyotyping analyses. T.I.S., A.A., and M.B. performed NGS, bioinformatics analysis, and variant interpretation. N.D., J.D., and S.F. performed clinical diagnosis, prognosis (disease staging), and clinical management of this patient, including therapeutic intervention. All authors contributed to the manuscript and approved the submitted version.

Funding

This study was supported by the Research Special Purpose Fund of the Department of Pathology, Allegheny Health Network.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Supporting information

Data Availability Statement

The data supporting the conclusions of this article are included within the article.