Successful treatment of relapsed KMT2A rearranged AML with central nervous system involvement using revumenib in combination with venetoclax and azacitidine: A case report

Abstract

This case report describes the successful treatment of a patient with acute monocytic leukemia (AML-M5), positive for the KMT2A::AFDN fusion gene, who relapsed and developed central nervous system involvement after allogeneic hematopoietic stem cell transplantation. The patient was a 32-year-old male initially treated with conventional chemotherapy followed by transplantation; however, he experienced relapse with AML infiltration of the CNS. Based on the MLL abnormality, salvage therapy was administered using the menin inhibitor Revumenib combined with venetoclax and azacitidine, followed by donor lymphocyte infusion (DLI). After one course of treatment, he achieved minimal residual disease (MRD)-negative status in both bone marrow and cerebrospinal fluid, with sustained complete remission. The main adverse effects observed were grade IV myelosuppression and grade II gastrointestinal symptoms. This case indicates that the salvage strategy incorporating Revumenib, venetoclax, azacitidine, and DLI not only exhibits potential for achieving deep remission in KMT2A-rearranged AML but also aids in controlling central nervous system infiltration, thereby providing a novel therapeutic direction for patients with relapsed AML. Further studies involving larger sample sizes are required to assess the long-term survival benefits of this strategy.

Plain language summary

This report describes a case of MLL-rearranged AML with central nervous system involvement who relapsed after transplantation. This patient achieved minimal residual disease (MRD)-negative status in bone marrow and cerebrospinal fluid after one course of Revumenib combined with venetoclax and azacitidine (VA regimen). Our case represents the first report that this three-drug combination regimen exerts favorable therapeutic efficacy in relapsed and refractory KMT2A-r AML with extramedullary involvement.

Introduction

Acute myeloid leukemia (AML) with lysine methyltransferase 2A (KMT2A/MLL1) gene rearrangements (KMT2A-r) is an aggressive disease with poor outcomes.^1,2 Median overall survival for this leukemic subtype is estimated to be 11.9 months, with a 5-year OS rate of 26%.^3,4 Even after allogeneic hematopoietic stem cell transplantation(allo-HSCT), the 5-year cumulative relapse rate remains as high as 65.7%. ⁵ High chemotherapy resistance and relapse risk are established as independent poor prognostic factors in AML. ⁶ Juul-Dam et al. ⁷ demonstrates that KMT2A-r causes blocked hematopoietic differentiation by abnormally activating the HOXA/MEIS1 pathway, leading to leukemic transformation. Revumenib inhibits AML proliferation by specifically targeting the menin-KMT2A protein interaction, effectively reducing HOXA/MEIS1 transcription levels, with encouraging outcomes. ⁸

This report describes a case of KMT2A -rearranged AML with central nervous system involvement who relapsed after transplantation. This patient achieved minimal residual disease (MRD)-negative status in bone marrow and cerebrospinal fluid after one course of Revumenib combined with venetoclax and azacitidine (VA regimen). Our case represents the first report that this three-drug combination regimen exerts favorable therapeutic efficacy in relapsed and refractory KMT2A-r AML with extramedullary involvement. The reporting of this study conforms to CARE guidelines. ⁹

Case presentation

An early-30s male patient was admitted to the Hematology Department of Nanfang Hospital in May 2022 (Day 0) due to persistent high fever (39.8°C), spontaneous gum bleeding, and respiratory infection. Laboratory tests showed leukocytosis (WBC 104.16×10⁹/L) and thrombocytopenia (PLT 117 × 10⁹/L).

Bone marrow aspiration showed 84% blast cells (Figure 1). Immunophenotyping revealed that 66.9% of the immature cells were positive for CD33, CD64, CD117, CD14 and MPO. A cytogenetic analysis showed a complex karyotype of 46–52,XY,+Y,−Y,del(1)(q21),+4,+4,+5,+6,−8,+9, del(11)(q23),+del(11)(q23),+11,+14,+14,+19,+21,+22[cp7]/46,XY ¹ (Figure 2), which resulted in the KMT2A rearrangement positivity (Figure 3) and KMT2A::AFDN fusion gene detected by PCR analysis. The analytical limit of detection for the KMT2A::AFDN PCR assay in our laboratory is 1 copy per 10^4 cells. Genetic mutations in TET2, RUNX1, and ASXL1 genes were also identified.

Figure 1.

Morphological of the bone marrow at initial diagnosis. Bone Marrow(BM): Blasts and immature monocytes accounted for 82%; POX: Predominantly granular positivity, with focal positivity in individual cells; PAS: Variably sized granular positivity; NAE: Positive in 12% of cells; NAF: Negative.

Figure 2.

Karyotype analysis of the patient.

Figure 3.

FISH was positive for KMT2A rearrangement.

Revumenib was not available at that time. Due to the high WBC count, hydroxyurea 2-3 g/day was administered for 7 days to reduce the leukocyte burden. The patient received standard IA induction chemotherapy idarubicin 12 mg/m² days 1–3) and cytarabine 200 mg/m² days 1–7), achieved morphological complete remission. However, flow cytometry detected minimal residual disease (MRD) at 0.41%, and quantitative PCR identified KMT2A::AFDN at a normalized ratio of 21.32 copies per 100 ABL1 copies.

Following consolidation with IA (idarubicin 10 mg/m² days 1–3 plus cytarabine 3 g every 12 hours days 1–3) and high-dose cytarabine (3.5 g every 12 hours days 1–3), MRD decreased to 0.31%, and KMT2A::AFDN became undetectable. Conventional intrathecal chemotherapy injection for preventing central nervous system leukemia (CNSL); with normal cerebrospinal fluid (CSF) analysis results. The regimen consisted of cytarabine 50 mg and dexamethasone 5mg administered intrathecally once per consolidation cycle.

The patient underwent BuCy (busulfan and cyclophosphamide) conditioning before receiving peripheral blood stem cells with a CD34+ cell dose of 3.4×106/kg, and the transplantation was smoothly. Immunosuppressants were discontinued by 9 months post-transplant without occurrence of chronic graft-versus-host disease. Up to 24 months post-transplant (September 2024), bone marrow examination was negative for MRD by flow cytometry and PCR, and showed complete donor chimerism.

At 32 months post-transplantation (May 2025), the patient was readmitted due to fever and headache. Bone marrow examination showed increased blasts (48.46%) and KMT2A::AFDN fusion transcript level was 26.54% by PCR. Immunophenotyping revealed that 25% of the immature cells were positive for CD33, CD64, CD117, CD14; and with mixed donor chimerism (72% donor). Magnetic resonance imaging (MRI) showed diffuse abnormal signal intensities involving the cervical vertebral bodies, adjacent soft tissues, and osseous structures (Figure 4), Additionally, Immunophenotyping revealed analysis of CSF detected 64% blasts cells (Figure 5). The patient developed AML relapse with central nervous system involvement.

Figure 4.

MRI image of the cervical spine during relapse.

Figure 5.

Flow cytometry report of cerebrospinal fluid during relapse. Approximately 4.44% of abnormal residual leukemia cells were detected, exhibiting a Leukemia-Associated Immunophenotype (LAIP) characterized by CD117(dim+), CD33(++), CD38(dim+), CD19(-), CD34(-), CD7(-), and HLA-DR(-).

The patient underwent salvage therapy with a combination of venetoclax plus azacitidine (VA) and the menin inhibitor (Revumenib) followed by donor lymphocyte infusion (DLI). The treatment regimen consisted of azacitidine 75 mg/m² on days 1–7, venetoclax 100 mg daily on days 1–14, and Revumenib 160 mg twice daily starting from day 6 (dose-adjusted due to concomitant use of the strong CYP3A inhibitor posaconazole);DLI (containing CD3⁺ T cells at a dose of 2.5 × 10⁶/kg) was administered 2 days after VA.

During therapy, the patient developed grade IV myelosuppression (ANC < 0.5 × 10⁹/L lasting 19 days), with infectious fever, grade II gastrointestinal symptoms (nausea and vomiting), and grade II hepatic impairment. No differentiation syndrome was observed. The patient achieved complete hematologic remission (CHR) 34 days after VA therapy, resulting in an MRD-negative by FCM and PCR (Figure 6), PET-CT imaging revealed no hypermetabolic lesions or evidence of bone destruction in the cervical spine (Figure 7), also with complete donor chimerism. Given definitive central nervous system (CNS) involvement, the patient received one cycle of intrathecal chemotherapy consisting of cytarabine 50 mg and dexamethasone 5 mg during the first consolidation therapy. Follow-up cerebrospinal fluid (CSF) examination confirmed negative measurable residual disease (MRD). As complete remission was achieved thereafter, further intrathecal treatment was withheld to minimize procedural toxicities. The patient continued to receive maintenance treatment with Revumenib without GVHD. The patient remained disease free for six months (December 2025). The timeline of this case was summarized in Figure 8.

Figure 6.

Quantitative status of KMT2A::AFDN during treatment(%) (All samples were derived from bone marrow).

Figure 7.

The whole-body PET-CT scan revealed no hypermetabolic lesions or evidence of bone destruction in the cervical spine.

Figure 8.

The treatment timeline of this patient.

Discussion

This case presents the first reported use of the menin inhibitor Revumenib in conjunction with the VA regimen for the treatment of a patient with relapsed KMT2A-rearranged AML with CNS involvement. After one treatment course, the patient achieved MRD negativity in both bone marrow and cerebrospinal fluid.

In KMT2A-rearranged AML, there is overexpression of the HOXA and MEIS1 gene clusters.^7,10,11 The underlying molecular mechanism entails the recruitment of histone methyltransferase DOT1L by KMT2A fusion proteins, which elevates histone H3 lysine 79 (H3K79) methylation levels and disrupts the balance of histone H3 lysine 4 (H3K4) methylation. ¹² These epigenetic perturbations alter chromatin architecture, activate leukemia-associated oncogenes, and ultimately drive leukemic cell proliferation. As a menin inhibitor, Revumenib targets the menin-KMT2A protein-protein interaction, thereby reducing HOXA/MEIS1 transcription and exerting potent anti-leukemic activity against AML cells, ⁷ which provides a mechanistic rationale for the observed treatment response. However, the AUGMENT-101 trial ¹³ reported that Revumenib monotherapy achieved CR/CRh rates of 24.5% (12/49) in relapsed or refractory KMT2A-r AML patients. It is suggested that there are other mechanisms involved in inducing drug insensitivity.

A study by Sharma et al. ¹⁴ demonstrated that Revumenib can indirectly downregulate MCL-1 expression, thereby reversing venetoclax resistance. Venetoclax exerts its cytotoxic effects by directly inhibiting the anti-apoptotic protein BCL-2, overcoming apoptosis evasion and inducing robust leukemic cell death. ¹⁵ Meanwhile, azacitidine functions by downregulating MCL-1 protein expression and upregulating the pro-apoptotic protein NOXA, thereby creating a cellular microenvironment conducive to apoptosis. This epigenetic modulation sensitizes AML cells to BCL-2 inhibition by venetoclax, eliciting a more direct and robust anti-leukemic response. ¹⁶ Moreover, Zeidner et al. ¹⁷ found that in elderly patients with newly diagnosed KMT2A-r AML, Revumenib combined with VA led to a 100% overall response rate (ORR) and 88.9% composite complete remission (CRc) rate, with all patients achieving MRD negativity by flow cytometry. This phase I trial shows encouraging results for this triplet combination in KMT2A-r AML. ¹⁷ In this case, the patient experienced recurrence after allo-HSCT, complete remission was achieved following treatment with this VA plus Revumenib.

Donor lymphocyte infusion (DLI) represents a pivotal salvage strategy for managing post-transplant relapse, primarily attributed to its potent graft-versus-leukemia (GVL) effect which mediates the eradication of residual malignant cells. Recently, Fetsch et al. ¹⁸ reported that menin inhibition enhances the graft-versus-leukemia (GVL)effect via the HERV/MHC-II axis in AML cells and promotes cytotoxicity of donor T cells, which provides a rationale for a clinical trial using menin inhibition as maintenance after allo-HCT. This patient remained in remission following VA plus Revumenib therapy, which may be attributable to the donor lymphocyte infusion (DLI) and subsequent Revumenib maintenance therapy. Donor lymphocyte infusion (DLI) augments the graft-versus-leukemia (GVL) effect through multiple immunological mechanisms. Primarily, the infused donor T cells directly recognize and eliminate residual host leukemic cells via alloreactivity against minor histocompatibility antigens or leukemia-specific antigens. ¹⁹ Furthermore, DLI stimulates the expansion of cytotoxic CD8+ T lymphocytes and natural killer (NK) cells, enhancing tumor lysis through perforin-granzyme pathways and death receptor signaling (e.g., Fas/FasL). Concurrently, donor T cells secrete pro-inflammatory cytokines, such as interferon-gamma and tumor necrosis factor-alpha, which modulate the bone marrow microenvironment to inhibit leukemic proliferation and promote antigen presentation, thereby sustaining a robust and durable anti-tumor immune response. ²⁰

Central nervous system leukemia relapse is relatively common and has a dismal prognosis in patients with AML. ²¹ Although evidence supporting the efficacy of Revumenib in the management of AML with central nervous system (CNS) involvement remains limited, however this patient represents the CNS invasion confirmed by CSF flow cytometry and imaging, with MRD turning negative following Revumenib combination therapy. These findings suggest that Revumenib may possess the capacity to cross the blood-brain barrier (BBB) and exert anti-leukemic activity within the CNS compartment, and that this triple-drug regimen holds promising therapeutic potential for high-risk AML patients complicated by CNS involvement. Considering the high baseline CNS tumor burden, a single course of intrathecal chemotherapy was administered upon the initiation of salvage therapy, whereas subsequent prophylactic intrathecal injections were discontinued. This clinical decision was supported by the rapid clearance of CSF MRD after the first treatment cycle. The observed CNS response raises the possibility that revumenib may contribute to disease control within the CNS; however, its CNS penetration and relative contribution cannot be established from this single case.

Regarding adverse effects, safety data from the AUGMENT-101 trial ¹³ demonstrated that QTc prolongation (23∽56%) and differentiation syndrome (16∽27%) are the most common adverse events associated with Revumenib treatment. In this case, we adhered to clinical safety guidelines by initially administering the VA regimen to reduce tumor burden, followed by the initiation of Revumenib on day 6, a strategy designed to mitigate the risk of differentiation syndrome. The primary adverse events observed in this patient included grade IV myelosuppression, accompanied by grade II gastrointestinal manifestations (vomiting) and grade II liver dysfunction. Notably, no QTc prolongation or differentiation syndrome. Hematological toxicity is a prevalent adverse event, affecting up to 87% of patients; dose adjustment of Revumenib is therefore recommended for patients with grade IV neutropenia or thrombocytopenia to optimize treatment tolerance. ¹⁷ Overall, the adverse effects associated with this triple-drug regimen were predictable and well manageable. Also, this study adopted a single-case design and the follow-up period was relatively short, which implies certain limitations.

Conclusion

This case represents the first reported use of Revumenib in conjunction with the VA regimen for successful treatment of a patient with relapsed KMT2A-rearranged AML with CNS involvement, and with continuous remission achieved through subsequent Revumenib maintenance therapy. Subsequent studies should focus on validating long-term survival benefits, especially for patients with CNS involvement, and warrants broader clinical evaluation.

ORCID iD

Jialiang Xu https://orcid.org/0000-0003-4438-1506

Consent to participate

The patient provided their consent for treatment.

Consent for publication

Written informed consent was obtained from the patient for the publication of this case report and any accompanying images. We have de-identified all patient details. All authors have read and approved the manuscript for publication.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request. For the original data, please contact sprenaa@163.com.