Methemoglobinemia in children with acute lymphoblastic leukemia (ALL) receiving dapsone forpneumocystis carinii pneumonia (PCP) prophylaxis: A correlation with cytochrome b5 reductase (Cb5R) enzyme levels

Williams, Suzan; MacDonald, Paula; Hoyer, James D.; Barr, Ronald D.; Athale, Uma H.

doi:10.1002/pbc.20164

Cited by 40 publications

(35 citation statements)

References 42 publications

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“…Our prevalence of confirmed methemoglobinemia cases approaches 20%, which is higher than what has been reported in the adult literature 3, but consistent with a rate of 20% previously observed in a much smaller cohort (N = 15) of pediatric oncology patients 4.…”

Section: Discussionsupporting

confidence: 92%

“…Twenty patients were required in each group to achieve 90% power. However, since the data by Williams demonstrated that mean difference in CYB5RA was 3.9 based on a small sample size (10 patients), we estimated the difference conservatively 4. Sample size computation was performed using PS software 11.…”

Section: Methodsmentioning

confidence: 99%

“…Decreased oxygen carrying capacity leads to severe hypoxia and cyanosis if not treated 3. The prevalence and associated risk factors for dapsone-associated methemoglobinemia in pediatric patients has not been well studied 1, 4–7. Cytochrome b5 reductase is an enzyme that reduces the toxic metabolite of dapsone (dapsone hydroxylamine) in the liver 8.…”

Section: Introductionmentioning

confidence: 99%

“…Cytochrome b5 reductase is an enzyme that reduces the toxic metabolite of dapsone (dapsone hydroxylamine) in the liver 8. Complete absence of cytochrome b5 reductase enzyme activity (CYB5RA) is associated with congenital methemoglobinemia, and its role in dapsone-associated methemoglobinemia has been postulated in a small case series 4. Using a large retrospective cohort, our study was designed to assess the prevalence of dapsone-assocatied methemoglobinemia as well as drug and host-related risk factors associated with increased risk of methemoglobinemia such as sex, age, body mass index (BMI), and dapsone dosing.…”

Section: Introductionmentioning

confidence: 99%

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Dapsone‐induced methemoglobinemia

Esbenshade

Shintani

et al. 2011

Cancer

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BACKGROUND: Dapsone, used for Pneumocystis jiroveci (PCP) prophylaxis, is associated with increased risk of methemoglobinemia. Absence of cytochrome b5 reductase enzyme activity causes congenital methemoglobinemia, but its role in dapsone-associated methemoglobinemia is unknown. The authors sought to elucidate drug-related risk factors for dapsone-associated methemoglobinemia in pediatric oncology patients, including contribution of cytochrome b5 reductase enzyme activity. METHODS: Among 167 pediatric patients treated for hematologic malignancies or aplastic anemia who received dapsone for PCP prophylaxis, demographic and dapsone treatment data were retrospectively collected. Drug-related risk factors were evaluated by Cox proportional hazards, and in a cross-sectional subgroup of 40 patients, cytochrome b5 reductase enzyme activity was assessed. RESULTS: Methemoglobinemia (median methemoglobin level ¼ 9.0% [3.5-22.4]) was documented in 32 (19.8%) patients. There was a 73% risk reduction in methemoglobinemia with dosing !20% below the target dose of 2 mg/kg/d (hazard ratio [HR], 0.27; 95% confidence interval [CI], 0.09-0.78; P ¼ .016), whereas methemoglobinemia risk was increased with dosing !20% above the target dose (HR, 6.25; 95% CI, 2.45-15.93; P < .001). Sex, body mass index, and age were not associated with increased risk. Cytochrome b5 reductase enzyme activity did not differ by methemoglobinemia status (median 8.6 IU/g hemoglobin [Hb]; [5.5-12.1] vs 9.1 IU/g Hb; [6.7-12.7]). No patient developed PCP on dapsone. CONCLUSIONS: Methemoglobinemia occurred in almost 20% of pediatric oncology patients receiving dapsone for PCP prophylaxis. Higher dapsone dosing is associated with increased risk. A cross-sectionally acquired cytochrome b5 reductase enzyme activity level was not associated with methemoglobinemia risk. Studies are needed to define biologic correlates of methemoglobinemia and evaluate lower dapsone doses for PCP prophylaxis. Cancer 2011;117: 3485-92.

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Section: Discussionsupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dapsone‐induced methemoglobinemia

Esbenshade

Shintani

et al. 2011

Cancer

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“…In large series, 5.8–20% of patients taking dapsone developed an increase in methemoglobinemia levels [13, 14]. Patients most at risk for dapsone-induced methemoglobinemia include anemic patients and the elderly, both of whom are frequently seen in neuro-oncology practice.…”

Section: Discussionmentioning

confidence: 99%

Dapsone induced methemoglobinemia in a patient with glioblastoma

et al. 2009

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Primary brain tumor patients have multiple risk factors for Pneumocystis jiroveci and may require prophylaxis with TMP-SMZ or dapsone. Although dapsone is generally safe and efficacious, we present a case of a patient diagnosed with a brain stem glioblastoma who developed methemoglobinemia and haemolytic anemia after presenting with worsening confusion and cardiopulmonary system dysfunction. This case highlights one of the potentially severe complications associated with dapsone therapy. Although this illustrates an unusual toxicity of dapsone, a high index of suspicion should be given to high-risk patients due to ethnic heritage, anemia, or advanced age. Furthermore, given the toxicities of TMP-SMZ and dapsone, further work is needed to determine the threshold CD4+ count at which empiric prophylaxis should be initiated.

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Recommendations for diagnosis and treatment of methemoglobinemia

et al. 2021

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Methemoglobinemia is a rare disorder associated with oxidization of divalent ferroiron of hemoglobin (Hb) to ferri-iron of methemoglobin (MetHb). Methemoglobinemia can result from either inherited or acquired processes. Acquired forms are the most common, mainly due to the exposure to substances that cause oxidation of the Hb both directly or indirectly. Inherited forms are due either to autosomal recessive

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Methemoglobinemia in children with acute lymphoblastic leukemia (ALL) receiving dapsone forpneumocystis carinii pneumonia (PCP) prophylaxis: A correlation with cytochrome b5 reductase (Cb5R) enzyme levels

Cited by 40 publications

References 42 publications

Dapsone‐induced methemoglobinemia

Dapsone‐induced methemoglobinemia

Dapsone induced methemoglobinemia in a patient with glioblastoma

Recommendations for diagnosis and treatment of methemoglobinemia

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