Does glucose‑6‑phosphate dehydrogenase (G6PD) deficiency increase the risk of lymphoma and require special screening or treatment considerations for lymphoma patients?

G6PD Deficiency and Lymphoma: No Increased Risk, But Critical Treatment Considerations

G6PD deficiency does not increase the risk of developing lymphoma and does not require special screening for lymphoma, but it creates absolute contraindications to several chemotherapy agents and supportive medications used in lymphoma treatment. 1, 2

Evidence on Lymphoma Risk

The relationship between G6PD deficiency and lymphoma development has been thoroughly investigated and shows no association:

• A case-control study in Sardinia examining 122 male lymphoma cases versus 116 controls found no association between G6PD deficiency (either self-reported phenotype or GdMed+ genotype) and lymphoma risk or any lymphoma subentity. 1

• A cohort study of 481 Sardinian males with hematological malignancies showed identical G6PD deficiency frequency compared to 16,219 controls, definitively ruling out any protective or risk-increasing effect. 2

• Analysis of 23 heterozygous women with clonal hematologic disease versus 37 healthy heterozygotes showed no difference in GdB gene expression frequency. 2

Critical Treatment Contraindications in Lymphoma Patients with G6PD Deficiency

Absolutely Contraindicated Chemotherapy Agents

• Rasburicase is absolutely contraindicated in G6PD deficiency because it causes simultaneous hemolytic anemia and methemoglobinemia, with documented cases showing hemoglobin drops from 14.8 to 5.3 g/dL and methemoglobin levels reaching 14.7%. 3, 4

• Screen all patients at risk for G6PD deficiency before administering chemotherapy for tumor lysis syndrome prophylaxis, particularly those of Mediterranean, African, Indian, or Southeast Asian descent. 5, 6, 4

Contraindicated Supportive Care Medications

• Dapsone is absolutely contraindicated as a potent oxidant causing methemoglobinemia and severe hemolysis by overwhelming G6PD reductive capacity. 5, 3

• Methylene blue (methylthioninium chloride) is absolutely contraindicated and can cause severe hemolytic anemia. 5, 3

• Primaquine is contraindicated in severe G6PD deficiency. 5, 3

Medications Requiring Caution

• NSAIDs including ibuprofen present moderate hemolysis risk and require close hemoglobin monitoring during use. 3

• Aspirin is explicitly contraindicated as it overwhelms the reduced antioxidant capacity in G6PD-deficient red blood cells. 3

Pre-Treatment Screening Algorithm

Before initiating lymphoma chemotherapy in at-risk populations:

1. Obtain quantitative G6PD testing (not qualitative spot tests) in all patients of Mediterranean, African, Indian, or Southeast Asian descent. 5, 6

2. Calculate percentage of normal activity by dividing the patient's G6PD value by the laboratory's upper limit of normal and multiplying by 100. 6

3. Interpret results based on variant severity:

   • <30% activity = severe deficiency (Mediterranean variant typical): absolute contraindication to all oxidant drugs 6
   • 30-70% activity = intermediate deficiency (African variant typical): modified regimens possible with close monitoring 6

   • 70% activity = adequate for most therapies 6

Critical Timing Pitfalls to Avoid

• Never test during or immediately after acute hemolytic episodes because reticulocytes and young RBCs contain near-normal enzyme levels, producing falsely elevated results that mask true deficiency. 6, 3

• Wait at least 50 days after RBC transfusion before performing enzyme assays, as donor RBC contamination of 6-12% causes false-negative results. 6

• Ensure proper red-cell purification (buffy coat removal or filtration) before analysis to eliminate white-cell and platelet interference. 6

Management of Hemolytic Crisis During Lymphoma Treatment

If hemolysis occurs during chemotherapy:

• Immediately discontinue the offending oxidant medication. 6

• Monitor hemoglobin closely and consider transfusion if hemoglobin drops below 7-8 g/dL with symptoms. 3

• For methemoglobinemia, use ascorbic acid (0.5-10 g) as the treatment of choice since methylene blue is contraindicated, despite ascorbic acid exceeding FDA-recommended doses for G6PD deficiency—the benefit outweighs hemolysis risk in life-threatening methemoglobinemia. 6

• Consider exchange transfusion for severe cases of hemolysis or rebound methemoglobinemia. 6

• Provide folic acid supplementation (1 mg daily) for patients with G6PD deficiency undergoing chemotherapy. 3

Alternative Pneumocystis Prophylaxis

Since dapsone is contraindicated:

• Use atovaquone or inhaled pentamidine for Pneumocystis prophylaxis in lymphoma patients with G6PD deficiency. 6

Safe Chemotherapy Options

• Penicillins (including amoxicillin) are not contraindicated and can be used in normal therapeutic doses. 3

• Standard lymphoma chemotherapy agents (cyclophosphamide, doxorubicin, vincristine) are not contraindicated by G6PD deficiency itself, though laboratory evidence suggests G6PDH overexpression may actually sensitize lymphoma cells to these agents. 7