Mucous Membrane Pemphigoid during CPX-351 Therapy Successfully Treated with Corticosteroids

Abstract

A 58-year-old man was diagnosed with acute myeloid leukemia with myelodysplasia-related changes. Induction therapy with CPX-351 achieved complete remission, and a second course of consolidation therapy was administered. Shortly after the second course, he developed aphthous ulcers on the tongue that progressively worsened. Although a tongue biopsy showed no specific findings, serum anti-bullous pemphigoid 180 antibodies were positive. Mucous membrane pemphigoid (MMP) was diagnosed, and corticosteroid therapy led to a rapid improvement. Given the temporal relationship between CPX-351 administration and the MMP onset, CPX-351 was considered to be the likely causative agent.

Introduction

Oral mucositis is a common complication of chemotherapy for acute myeloid leukemia (AML). The causes include drug-induced, infectious, neoplastic, and autoimmune conditions (1). Chemotherapy-induced oral mucositis has been reported in 21.9% of patients (2), while the incidence of oral infection during AML treatment is 20.4% (3). Therefore, infections and drug-induced causes are considered to be the most common etiologies of oral mucositis during AML treatment.

CPX-351 is a liposomal formulation that combines daunorubicin and cytarabine at a fixed 1:5 molar ratio (4). In domestic and international clinical trials, oral mucositis has not been reported as a frequent or severe adverse event (5,6). To our knowledge, no previous case report has described severe mucosal injury following CPX-351 administration.

Pemphigoid is an antibody-mediated autoimmune blistering disease characterized by linear deposition of autoantibodies along the epidermal basement membrane zone, resulting in subepidermal blister formation. It includes bullous pemphigoid (BP), which primarily affects the skin, and mucous membrane pemphigoid (MMP), which mainly affects the mucosal sites. The target antigens include BP180 and laminin-332 in the basement membrane zone, and an association with malignancy has been suggested (7,8).

We herein report a case of severe mucosal injury that developed during consolidation therapy with CPX-351. The lesion was initially suspected to be infectious but was unresponsive to treatment, and the condition was ultimately diagnosed as MMP. Corticosteroid therapy resulted in marked clinical improvement.

Case Report

A 58-year-old man was referred to our hospital for a further evaluation because blasts accounted for 68% of the peripheral blood leukocytes. A bone marrow examination revealed dysplastic changes in the two hematopoietic lineages, leading to a diagnosis of AML with myelodysplasia-related changes. Therefore, induction therapy with CPX-351 was initiated. A post-induction bone marrow evaluation confirmed hematologic remission, and peripheral blood Wilms Tumor 1 mRNA levels decreased to ＜50 copies/μg RNA. However, he developed pulmonary aspergillosis and underwent left upper lobectomy. After his general condition had improved, he was hospitalized for consolidation therapy.

CPX-351 was administered at 65 units/m² on days 1 and 3 (Fig. 1). From day 3, erythema appeared on both thighs but resolved spontaneously by day 15. On day 20, the patient developed a sore throat, and laryngopharyngeal endoscopy revealed several aphthous ulcers at the left base of the tongue (Fig. 2A-C). By day 28, the sore throat had worsened, and multiple aphthous ulcers were observed in the epiglottis and pharynx (Fig. 2D-F). The lesions were clinically diagnosed as infectious mucosal injuries and antimicrobial therapy was administered; however, no improvement was observed. By day 39, the aphthous ulcers had extended from the epiglottis to the lip. Continuous intravenous morphine infusion was initiated for pain control; however, the pain remained poorly controlled, and oral intake became impossible (Fig. 2G-I). A tongue biopsy revealed no significant pathological findings; however, serum anti-BP180 antibodies were positive (Fig. 3). Based on the clinical course, MMP was diagnosed, and hydrocortisone (200 mg/day) was administered.

Figure 1.

Clinical course. ACV: Acyclovir, CFPM: Cefepime, HC: Hydrocortisone, ISCZ: Isavuconazole, L-AMB: Lipo-somal Amphotericin B, LVFX: Levofloxacin, MCFG: Micafungin, mPSL: Methylprednisolone, PIPC/TAZ: Piperacillin/ Tazobactam, WBC: White Blood Cell

Figure 2.

Endoscopic findings of mucosal lesions. A-C) Endoscopic findings at the initial examination (day 21). A shows the larynx, B the pharynx, and C the tongue and lips. A few aphthous lesions were observed in the pharynx. D-F) Endoscopic findings on day 28. D displays the larynx, E the pharynx, and F the tongue and lips. Mucosal lesions had extended from the pharynx to the epiglottis. G-I) Endoscopic findings on day 39. G shows the larynx, H the pharynx, and I the tongue and lips. Mucosal lesions had further extended from the lips to the epiglottis. J-L) Endoscopic findings on day 51. J displays the larynx, K the pharynx, and L the tongue and lips. Although epiglottic cartilage exposure persisted, the mucosal lesions had improved. M, N) Endoscopic findings on day 67. M shows the larynx and N the pharynx. Exposure of the epiglottic cartilage had improved.

Figure 3.

Summary of laboratory tests. BP: Bullous pemphigoid, CMV: Cytomegalovirus, DNA: Deoxyribonucleic Acid, HIV: Human Immunodeficiency Virus, HSV: Herpes Simplex Virus, PRP: Rapid Plasma Reagin, TPHA: Treponema pallidum Hemagglutination, T-SPOT. TB: T-SPOT Tuberculosis test, VZV: vari cella-zoster virus

After initiating hydrocortisone treatment, his symptoms rapidly improved, and an endoscopic examination on day 51 showed complete resolution of the aphthous ulcers (Fig. 2J-L). No recurrence was observed after tapering corticosteroids, and the patient was discharged on day 68 (Fig. 2M, N). After consolidation therapy, the patient underwent allogeneic hematopoietic stem cell transplantation. Corticosteroids were continued during the transplantation period, anti-BP180 antibodies were negative, and there was no recurrence of oral mucositis.

Discussion

The differential diagnosis of refractory oral lesions includes infectious, drug-induced, neoplastic, and autoimmune causes (1). All cultures, viral genes, and fungal antigen tests were negative. Furthermore, antimicrobial, antiviral, and antifungal therapies are ineffective, making infectious etiology unlikely. A tongue biopsy revealed no evidence of neoplastic lesions. No new medications were administered during hospitalization for drug-induced mucosal injury. Although mucosal toxicity caused by CPX-351 was considered, the reported incidence of mucositis with CPX-351 was 22%, with grade ≥3 events occurring in only 3% of patients (9). Furthermore, no cases of severe mucosal injury similar to the current case have been reported. In addition, because no skin lesions were observed during the appearance of mucosal injury and the diagnostic criteria for severe drug eruptions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis, were not met (10), a drug eruption was considered unlikely.

The diagnosis of MMP is based on clinical manifestations, direct immunofluorescence of biopsy specimens, and serological testing. However, international guidelines do not provide a specific scoring system (7). According to the Japanese guidelines, a “Definite” diagnosis can be made when three criteria are met: (1) clinical features, including non-infectious blisters and erosions on mucosal sites such as the oral mucosa, (2) histopathological findings, including subepidermal blisters, and (3) immunological findings, such as the detection of circulating anti-BP180 antibodies. In the present case, serum anti-BP180 antibodies were positive, and blistering lesions were observed on the mucosal surfaces, including the oral mucosa, without accompanying skin lesions, suggesting MMP as a differential diagnosis. Although a histopathological examination did not reveal characteristic subepidermal blister formation due to tissue degeneration and direct immunofluorescence could not be performed at our institution, the diagnostic criteria for MMP were not fully met. Nevertheless, other diseases were ruled out and, based on the clinical course, an MMP diagnosis was established.

For MMP, the sensitivity of anti-BP180 antibodies has been reported to be 50%, with a specificity of 83.3%, suggesting that a positive anti-BP180 antibody result is clinically meaningful for the diagnosis of MMP (11). Corticosteroid therapy was initiated, and the patient exhibited a favorable response. MMP treatment is stratified according to disease severity as low risk (localized oral mucosal±cutaneous lesions) or high risk (extensive or progressive oral mucosal lesions or involvement of the eyes, genitalia, nasopharynx, larynx, or esophagus). In the present case, extensive and progressive mucosal lesions extending from the lips to the larynx were classified as high risk. For patients in the high-risk group with severe disease, corticosteroid therapy and immunosuppressive agents such as cyclophosphamide or methotrexate are recommended. As oral administration was not feasible in the present patient, intravenous corticosteroid therapy was administered (12).

Pemphigoids are associated with malignancies and use of certain medications. In leukemia, BP has been reported as a paraneoplastic manifestation at the onset of AML, with improvement parallel to leukemia remission (13). Nonetheless, in the present case, mucosal lesions developed while AML was in complete remission, making paraneoplastic BP unlikely. Drug-induced pemphigoid has been associated with loop diuretics and dipeptidyl peptidase-4 inhibitors (14,15), the patient did not receive these agents. Although no reports to date have demonstrated an association between CPX-351 and MMP, the possibility that CPX-351 is related to the development of MMP cannot be excluded, given the clinical context, even though the precise mechanism remains unclear.

In conclusion, MMP can develop during CPX-351 treatment. In cases of refractory mucosal lesions or autoimmune mucosal disorders, including MMP, the differential diagnosis should include autoimmune mucosal disorders, and prompt initiation of immunosuppressive therapy, such as corticosteroids, is crucial for a favorable prognosis.

Written informed consent was obtained from the patient.

The authors state that they have no Conflict of Interest (COI).