Dapsone-induced methemoglobinemia in gynecologic cancer patients treated with immune checkpoint Inhibitors: a case series

Highlights

• •Management of adverse events from immune checkpoint inhibitors involves Pneumocystis jirovecii pneumonia prophylaxis.
• •Dapsone, an antibiotic used for Pneumocystis jirovecii pneumonia prophylaxis, can cause methemoglobinemia.
• •Clinical overlap in the presentation of methemoglobinemia and ICI pneumonitis creates a unique diagnostic challenge.
• •Prompt recognition of methemoglobinemia is essential for mitigation of morbidity and mortality of the diagnosis.

Abstract

Background

Immune checkpoint inhibitors (ICI) activate antitumor immunity which can lead to the development of immune-related adverse events (irAE) that often require management with high-dose corticosteroids. The dosing and duration of corticosteroid therapy necessitates antibiotic prophylaxis against Pneumocystis jirovecii pneumonia (PJP). In patients that cannot use first-line trimethoprim–sulfamethoxazole, dapsone is a common alternative. A rare, serious complication of dapsone use is methemoglobinemia. Here, we present a case series of 3 gynecologic oncology patients on PJP prophylaxis with dapsone for irAEs related to ICI therapy who developed acquired-methemoglobinemia.

Methods

This is a case series and review of literature. Patient consent was obtained prior to initiation of the series and submission to the journal.

Objective

This case series describes three gynecologic oncology patients on ICI therapy who, while receiving dapsone for PJP prophylaxis during corticosteroid treatment for irAEs, presented to care with hypoxia and nonspecific symptoms. The presence of persistent hypoxia despite oxygen supplementation increased clinical suspicion of a dyshemoglobinemia and co-oximetry confirmed methemoglobinemia. Dapsone, the offending agent, was discontinued and patients were supportively managed with one patient additionally receiving methylene blue. This series aims to highlight the diagnostic challenges, overlap with ICI pneumonitis, and key management considerations.

Conclusions

Dapsone-induced methemoglobinemia is an important diagnostic consideration in gynecologic oncology patients on ICIs, particularly when faced with refractory hypoxia despite appropriate management of presumed immune-related toxicity. Recognition of acquired methemoglobinemia’s characteristic laboratory features and timely cessation of dapsone are vital to ensuring accurate diagnosis and to optimizing patient outcomes.

1. Introduction

Immune checkpoint inhibitors (ICI) are increasingly used in gynecologic cancers due to improved progression-free and overall survival in advanced or recurrent disease. Because ICIs activate endogenous antitumor immunity, up to 40% of patients develop immune-related adverse events (irAEs) (Gumusay et al., 2022, Schneider et al., 2021). Management of moderate to severe irAEs typically requires high-dose corticosteroids with a gradual taper over several weeks. When corticosteroids exceed ≥20 mg prednisone daily for ≥4 weeks, prophylaxis for opportunistic infections, particularly Pneumocystis jirovecii pneumonia (PJP), is indicated. Trimethoprim–sulfamethoxazole (TMP-SMX) is first-line, but dapsone is often used for sulfonamide allergies or intolerance (National Comprehensive Cancer Network, 2024). Dapsone can cause a rare, yet serious, complication of methemoglobinemia in which hemoglobin iron is oxidized from the ferrous to ferric state, impairing oxygen binding and limiting delivery of oxygen to tissues (Ludlow et al., 2023). This case series describes three gynecologic oncology patients on ICI therapy who developed dapsone-induced methemoglobinemia during corticosteroid treatment for irAEs, highlighting diagnostic challenges, overlap with ICI pneumonitis, and key management considerations (Table 1).

Table 1.

Clinical characteristics, diagnostic timeline, and management of patients who developed methemoglobinemia after dapsone administration for Pneumocystis jirovecii pneumonia (PJP) prophylaxis while undergoing immune checkpoint inhibitor therapy for endometrial cancer.

	Case 1	Case 2	Case 3
Age (Years)	71	75	69
Diagnosis	Recurrent endometrial cancer	Stage IIIC1 endometrial cancer	Recurrent endometrial cancer
Immunotherapy	Lenvatinib / Pembrolizumab	Dostarlimab	Ipilimumab / Nivolumab
iRAE	Dermatitis, Colitis	Pneumonitis	Colitis
Reason For Dapsone	Sulfonamide allergy	Sulfonamide allergy	Hyperkalemia with TMP-SMX
Presenting Symptoms	hypoxia, blurry vision	SOB, hypoxia	tachycardia, hypoxia
Time From Dapsone Initiation To Presenting Symptoms	6 days	N/A*	17 days
Time From Dapsone Initiation To MethHb Diagnosis	9 days	5 days	17 days
Admission MethHb Level (%)	13.7	8.9	6.5
Admission ABG Ph	7.53	7.37	7.47
Admission Po2	179	114	168
G6PD Activity	Present	Present	Present
Methylene Blue Treatment	No	No	Yes
Discharge PJP Prophylaxis	No	No	Atovaquone
Length Of Hospitalization	2 days	9 days	7 days

^*Dapsone initiated after admission for ICI pneumonitis.

2. Case 1

A 71-year-old woman with recurrent mismatch-repair proficient (pMMR) endometrial cancer presented for lenvatinib/pembrolizumab (cycle 4) reporting nocturnal hypoxia to 84% and blurred vision. She had a history of bilateral lobectomies and stereotactic body radiotherapy to the lungs for prior treatment of recurrent disease. She had recently been hospitalized for grade ≥3 ICI colitis and dermatitis and was discharged on high-dose prednisone and dapsone for PJP prophylaxis due to a sulfonamide allergy. On admission, oxygen saturation was 85% on room air, requiring up to 6 L of high-flow oxygen to maintain SpO₂ ≥ 90%. Initial evaluation revealed pH 7.53, PaO₂ 179 mmHg, normal bicarbonate, B-type natriuretic peptide 2434 pg/mL, and methemoglobin 13.7%. Imaging showed no thromboembolic event. Because of the elevated methemoglobin and a PaO₂–saturation gap, co-oximetry confirmed oxyhemoglobin 85% and methemoglobinemia. Dapsone was discontinued. Pulmonology advised against methylene blue due to low MetHb level, minimal symptoms, and unknown G6PD status (later found to be normal). Serial co-oximetry every 6–8 h showed improvement. She was weaned to room air and discharged on hospital day 3. Steroid taper was continued without PJP prophylaxis.

3. Case 2

A 75-year-old female with stage IIIC1 mismatch-repair deficient (dMMR) endometrial cancer on maintenance dostarlimab (cycle 12) presented with fatigue and exertional dyspnea and was hypoxic to <90%, requiring 2 L of oxygen. Examination demonstrated diminished breath sounds and bilateral basilar inspiratory crackles. Laboratory studies were unremarkable. Imaging showed bilateral pleural effusions and consolidations concerning for pneumonia and a large pulmonary embolism. She was started on anticoagulation and high-dose steroids (1 mg/kg) for suspected ICI pneumonitis. Because of a sulfa allergy and prolonged steroid use, dapsone prophylaxis was initiated. Despite treatment, oxygen requirements escalated with little subjective dyspnea. On hospital day 5, steroids were increased (2 mg/kg) and empiric antibiotics were started. Pulmonology was consulted due to persistent severe hypoxia despite high-dose steroids. Co-oximetry showed oxyhemoglobin 57%, methemoglobin 8.9%, and O₂ saturation 64%, confirming methemoglobinemia. Dapsone was discontinued. G6PD enzyme activity was normal, but methylene blue was deferred. Serial co-oximetry guided oxygen titration. She ultimately received two doses of rituximab for steroid-refractory ICI pneumonitis and was discharged on hospital day 10 on a steroid taper without PJP prophylaxis.

4. Case 3

A 69-year-old female with recurrent endometrial adenocarcinoma being treated with ipilimumab/nivolumab (cycle 3) presented 2 weeks after hospitalization for grade 3–4 ICI colitis treated with IV steroids. She had been discharged on a steroid taper and dapsone for PJP prophylaxis after developing hyperkalemia due to acute kidney injury with TMP-SMX. Although asymptomatic at follow-up, she was found to be hypoxic to 82% with tachycardia. In the emergency department, she remained without distress but hypoxic despite escalation to a non-rebreather mask. Chest imaging was unremarkable. Concern for methemoglobinemia prompted arterial co-oximetry, which showed pH 7.47, PaO₂ 168 mmHg, lactate 3.1 mmol/L, oxyhemoglobin 90%, and methemoglobin 6.5%. As patient had recently undergone G6PD testing demonstrating the presence of the enzyme, the emergency department administered two doses of IV methylene blue at a dose of 1 mg/kg. She was transitioned to atovaquone for PJP prophylaxis and was admitted for serial ABG and methemoglobin trend. She was weaned to room air was and discharged on hospital day 6.

5. Discussion

5.1. Understanding the condition and relevance to gynecologic oncology

Methemoglobinemia can be congenital but more commonly is acquired due to exposure to oxidizing medications, with dapsone being one of the most common causes (Barclay et al., 2011). Dapsone is among the most frequent causes of acquired methemoglobinemia despite the overall rarity of the condition; its metabolite, dapsone hydroxylamine, generates oxidative stress that exceeds the capacity of the cytochrome-b5 reductase pathway, leading to progressive methemoglobin accumulation and impaired oxygen delivery (Ludlow et al., 2023, Belzer and Krasowski, 2024, Skold et al., 2011).

Dapsone-induced methemoglobinemia is a rare but serious diagnosis. Although symptomatic methemoglobinemia is uncommon, measurable elevations in methemoglobin occur in approximately 15–20% of patients receiving standard oral dapsone, and dapsone remains the most commonly identified culprit in retrospective series of acquired methemoglobinemia (Singh et al., 2014, Khan Suheb et al., 2022). Specifically, in a large single academic center retrospective review of patients with acquired methemoglobinemia, dapsone was the most frequent cause in both pediatric and adult populations (73.3% and 65.3% respectively) (Belzer and Krasowski, 2024). Risk is increased with higher doses or prolonged exposure, reduced body weight, renal or hepatic dysfunction, concomitant use of other oxidizing agents, and underlying red-cell enzymatic defects such as G6PD deficiency or cytochrome-b5 reductase deficiency (Singh et al., 2014, Khan Suheb et al., 2022).

In gynecologic oncology patients receiving ICIs, diagnosis of dapsone-induced methemoglobinemia is further complicated by its overlapping presentation with immune-related pneumonitis (Table 2). Both conditions may present with new or worsening hypoxia, dyspnea, or nonspecific constitutional symptoms, and up to one-third of patients with pneumonitis may be asymptomatic aside from hypoxemia (Gumusay et al., 2022, Lin et al., 2024). As a result, clinicians may understandably anchor on an immune-related etiology, particularly when patients are already being treated for other irAEs with high-dose corticosteroids.

Table 2.

Comparative and contrasting clinical and diagnostic features of immune checkpoint inhibitor (ICI) pneumonitis versus dapsone-induced methemoglobinemia.

	ICI Pneumonitis	Methemoglobinemia
Symptoms	dyspnea/tachypnea nonproductive coughweight loss	dyspnea/tachypnea headache fatigue, weakness confusion, altered mental status nausea/vomiting chest painseizures
Exam Findings	responsive hypoxiabibasilar crackles	refractory hypoxiacentral cyanosis
Labs	high inflammatory markers (IL-6, NLR) low serum albuminBAL high lymphocytes	high anion gap metabolic acidosis normal or high PaO2 Elevated methemoglobin levelselevated troponin
Imaging	patchy consolidations ground glass opacities reticular markings traction bronchiectasiswidespread airspace opacities	No findings
Treatment	Oxygen therapyCorticosteroid therapy (must be slow, 4–6 week)	IV hydration High flow oxygen therapy Methylene blue Ascorbic acid
Clinical Pearls	Will improve with O2 therapyMust rule out infection before steroids	Blood sample with chocolate brown color despite air/oxygen exposure due to diminished oxygen carrying capacitySuspect in any IO patient on prednisone + dapsone presenting with hypoxia

5.2. Diagnosis

Diagnosing methemoglobinemia in patients receiving immune checkpoint inhibitors and dapsone prophylaxis requires careful interpretation of oxygenation and laboratory data because symptoms are often nonspecific (Ludlow et al., 2023, Skold et al., 2011, Lin et al., 2024). The defining physiologic feature is hypoxemia that does not improve with escalating supplemental oxygen (Ludlow et al., 2023, Skold et al., 2011, Bura et al., 2025, Iolascon et al., 2021). When pulse oximetry values remain low despite high-flow oxygen or a non-rebreather mask, a hemoglobin abnormality should be considered, as most pulmonary causes of hypoxia demonstrate at least partial correction with increased inspired oxygen (Akhtar et al., 2007).

A second key element is the presence of a saturation gap, defined as a difference greater than 5% between the oxygen saturation measured by pulse oximetry and the saturation calculated from an arterial blood gas (Barclay et al., 2011, Singh et al., 2014, Akhtar et al., 2007). Pulse oximetry relies on two-wavelength spectrophotometry and cannot distinguish methemoglobin from oxyhemoglobin, leading to artifactually depressed or fixed readings. By contrast, ABG-derived oxygen saturation is calculated from the measured PaO₂ and the oxyhemoglobin dissociation curve is not affected by methemoglobin. A measurable gap between these values strongly suggests a dyshemoglobinemia (Akhtar et al., 2007).

The arterial blood gas provides additional diagnostic information. Patients with methemoglobinemia typically have a normal or even markedly elevated PaO₂ because dissolved oxygen in the plasma remains available even though hemoglobin cannot effectively bind or transport it (Barclay et al., 2011, Skold et al., 2011). This pattern of a high PaO₂ in the setting of persistent hypoxia is inconsistent with structural lung diseases and should heighten suspicion for a hemoglobin-based cause of impaired oxygen delivery (Barclay et al., 2011, Skold et al., 2011).

Co-oximetry is required for definitive diagnosis (Bura et al., 2025, Barclay et al., 2011, Belzer and Krasowski, 2024). Unlike pulse oximetry or standard ABG calculations, co-oximeters use multiple wavelengths to directly quantify oxyhemoglobin, deoxyhemoglobin, carboxyhemoglobin, and methemoglobin. Normal methemoglobin levels are approximately 1%, and elevations above this value are diagnostic (Ludlow et al., 2023, Akhtar et al., 2007). Levels above 10% typically correlate with symptomatic hypoxia, though susceptibility varies by patient and comorbidities with increased vulnerability to severe effects noted in those with preexisiting anemia or cardiovascular disease (Ludlow et al., 2023, Barclay et al., 2011, Belzer and Krasowski, 2024). Serial co-oximetry is useful to monitor progression and response to treatment, especially when dapsone’s long-acting metabolites may continue to generate oxidative stress (Ludlow et al., 2023, Mack, 2007).

In the overlapping clinical presentation of immune related pneumonitis and methemoglobinemia, as seen in patients on ICIs and dapsone prophylaxis, key diagnostic distinguishers are the presence of refractory hypoxemia and a saturation gap. A pulse oximetry measurement that remains unresponsive to supplemental oxygen uptitration is atypical for IO pneumonitis and should prompt evaluation for alternative etiologies. Pneumonitis usually demonstrates radiographic abnormalities, whereas imaging is normal in methemoglobinemia (Schneider et al., 2021, Lin et al., 2024). ICI-related pneumonitis also lacks a saturation gap and is typically associated with impaired gas exchange leading to a low or normal PaO₂, in contrast to the normal or elevated PaO₂ seen in methemoglobinemia (Lin et al., 2024). Because these two conditions may coexist, persistent or unexplained hypoxia in patients receiving immunotherapy and dapsone prophylaxis should prompt evaluation for methemoglobinemia, particularly when clinical improvement does not occur as expected.

5.3. Management

Management of acquired methemoglobinemia begins with discontinuation of the offending agent, as cessation of dapsone removes ongoing oxidative stress that drives continued methemoglobin formation. Supportive measures should be initiated, including supplemental oxygen and intravenous hydration (Barclay et al., 2011, Iolascon et al., 2021). Although supplemental oxygen does not correct the underlying defect in hemoglobin function or reverse cyanosis, it increases the dissolved oxygen content in plasma and helps mitigate tissue hypoxia (Ludlow et al., 2023). Intravenous fluids can correct accompanying metabolic derangements such as acidosis and support renal clearance of dapsone metabolites (Ludlow et al., 2023, Bura et al., 2025).

Patients with mild elevations in methemoglobin, particularly those with levels below 20% and without significant symptoms, often improve with supportive care alone (Bura et al., 2025). Endogenous reduction pathways, primarily mediated by cytochrome-b5 reductase, gradually restore functional hemoglobin once the oxidant load has ceased. Improvement typically occurs over several hours to days, and close clinical monitoring is essential to ensure that methemoglobin levels continue to decline (Bura et al., 2025, Iolascon et al., 2021). Ascorbic acid may be considered in mild cases and in patients with G6PD deficiencies. It reduces oxidative stress and reduces MetHb levels, but requires multiple doses and has no standardized dosing regimen outlined in the literature (Iolascon et al., 2021).

Pharmacologic intervention is indicated for patients with significant symptoms or with methemoglobin levels exceeding 20%(Bura et al., 2025, Iolascon et al., 2021). Methylene blue is the preferred treatment;(Iolascon et al., 2021). It acts by providing an alternative reduction pathway in which methylene blue, once reduced to leucomethylene blue, facilitates the conversion of ferric iron back to its functional ferrous form (Bura et al., 2025, Iolascon et al., 2021). Standard dosing consists of 1 to 2 mg/kg administered intravenously over several minutes, and clinical improvement is usually observed within an hour (Bura et al., 2025, Iolascon et al., 2021). A second dose may be administered if methemoglobin levels do not fall appropriately or if symptoms persist. Because dapsone metabolites have long half-lives and can continue to generate oxidative stress, repeat dosing every 6 to 8 h may be necessary (Bura et al., 2025, Iolascon et al., 2021). In severe or refractory cases, more aggressive interventions may be required. Exchange transfusion can be used in patients with critically high methemoglobin levels or in those who fail to improve with standard therapy. Mechanical ventilation and vasopressor support may be necessary in the setting of profound hypoxia, hemodynamic instability, or end-organ dysfunction (Bura et al., 2025, Iolascon et al., 2021).

Prior to administering methylene blue, screening for glucose-6-phosphate dehydrogenase (G6PD) deficiency is necessary. Patients with G6PD deficiency lack the ability to generate sufficient NADPH to reduce methylene blue to its active form. Accordingly, methylene blue may precipitate hemolysis and worsen methemoglobinemia (Barclay et al., 2011, Iolascon et al., 2021). Ideally, G6PD status should be established before initiating dapsone. In patients in whom methylene blue is contraindicated, high-dose ascorbic acid may be considered (Iolascon et al., 2021). Caution should be employed in patients taking serotonergic antidepressants as methylene blue inhibits monoamine oxidase (Barclay et al., 2011, Iolascon et al., 2021). Methylene blue is not recommended in patients with renal failure, as it may result in systemic and pulmonary hypertension (Iolascon et al., 2021).Treatment response is monitored through serial co-oximetry to document declining methemoglobin levels and guide additional therapy (Iolascon et al., 2021). Concurrent management of metabolic acidosis, careful hemodynamic monitoring, and close observation for cardiac or neurologic complications are essential, as impaired oxygen delivery increases the risk of ischemic events (Iolascon et al., 2021). Despite the high risk of morbidity and mortality with increasing methemoglobin concentration, methemoglobinemia is treatable and overall prognosis is favorable with prompt recognition and management (Ludlow et al., 2023, Belzer and Krasowski, 2024). Long-term sequelae is unlikely but, if present, is related to tissue hypoxia (Ludlow et al., 2023). Once resolved, patients should be re-evaluated regarding the need for ongoing Pneumocystis jirovecii pneumonia prophylaxis, as alternative agents such as atovaquone or aerosolized pentamidine may be preferable to avoid recurrence of oxidant injury (Troung and Ashurst, 2023).

5.4. Conclusion

This case series underscores that dapsone-induced methemoglobinemia is an uncommon but important diagnostic consideration in gynecologic oncology patients on immune checkpoint inhibitors, particularly when hypoxia persists despite appropriate management of presumed immune-related toxicity. Recognition of its characteristic laboratory features and timely cessation of dapsone are critical to ensuring accurate diagnosis and to optimizing patient outcomes.

Patient consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

CRediT authorship contribution statement

Julia C. Sakach: Writing – review & editing, Writing – original draft, Visualization, Methodology, Investigation. Sydney Anderson: Writing – original draft, Investigation. Cassidy Abdeen: Writing – original draft, Visualization, Investigation. Danielle Glassman: Writing – review & editing, Methodology, Conceptualization. Casey M. Cosgrove: Writing – review & editing. Robert T. Neff: Writing – review & editing. Laura J. Chambers: Writing – review & editing, Supervision, Project administration, Conceptualization.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.