Use of Doxorubicin-Containing Regimens Is Not Associated with Hemolytic Complications in Severely G6PD Deficient Patients with Lymphoma

Background

G6PD deficiency is the most common enzymatic deficiency in humans and is widely prevalent in the Middle East with a reported prevalence of 26% in Bahrain. There are conflicting reports linking G6PD deficiency to oxidative hemolysis with doxorubicin. Some physicians treating severely G6PD deficient lymphoma patients substitute etoposide for doxorubicin in regimens such as CHOP and ABVD, however practices vary widely among hematologists in the Middle-East. There are no retrospective or prospective studies evaluating safety of doxorubicin in this specific group of patients.

Aims

To assess hemolytic complications in lymphoma patients with severe G6PD deficiency receiving doxorubicin containing regimens.

Methods

This study was conducted in 2 parts- we did an initial retrospective pilot study among lymphoma patients treated in our center from Jan 2018 to Mar 2021. We included patients with Hodgkin lymphoma and diffuse large B-cell non-Hodgkin lymphoma (DLBCL) who received curative intent treatment. Severe G6PD deficiency was defined as enzymatic activity of less than 10%. All patients were of Middle-Eastern ethnicity.

The primary outcome measure was the occurrence of hemolysis among severely G6PD deficient patients who received doxorubicin. Secondary outcome measures were overall and event-free survival (OS and EFS) in patients where etoposide was substituted for doxorubicin in R-CHOP or ABVD regimens.

After confirming the safety of doxorubicin in the pilot study we then prospectively collected data on severely G6PD deficient lymphoma patients treated between Apr 2021 to Dec 2023 to look for occurrence of clinical or laboratory hemolysis after receiving doxorubicin-containing regimens (ABVD, A-AVD, R-CHOP or EPOCH-R). Patients underwent systematic screening for clinical and laboratory hemolysis for the first three days after receiving doxorubicin-based chemotherapy. This study was approved by our institutional review board.

Results

In the retrospective pilot study we studied 177 patients, of whom 28 (16%) were severely G6PD deficient.

Of 95 patients in the Hodgkin lymphoma sub-group, seventeen percent were severely G6PD deficient, however only five percent had received EBVD regimen instead of ABVD. We observed comparable 2-yr OS and EFS with ABVD and EBVD regimens. Eleven severely deficient patients in the Hodgkin lymphoma subset (11.5%) had received ABVD, and none had documented hemolytic complications.

Of 82 patients in the DLBCL sub-group, fifteen percent were severely G6PD deficient, and ten percent had received R-COEP instead of R-CHOP regimen. Patients who received R-COEP had inferior 2-yr OS (HR 5.7, 95% CI-2.08-15.8) and inferior 2-yr EFS (HR-3.3, 95% CI- 1.3-8.2) compared to the R-CHOP group. Seven severely deficient patients in the B cell lymphoma subset (9.5%) had received R-CHOP, none had hemolytic complications documented.

Based on the safety profile observed in the pilot study, we then prospectively studied 214 lymphoma patients from Apr 2021 to Dec 2023, of whom thirty-nine patients (18.2%) had severe G6PD deficiency. Fourteen severely G6PD deficient patients with Hodgkin lymphoma received ABVD/A-AVD regimens while twenty-five severely deficient DLBCL patients received R-CHOP/EPOCH-R regimens. None of these patients had clinical or laboratory evidence of hemolysis on short-term follow-up.

Summary

The use of doxorubicin was not associated with hemolytic complications in lymphoma patients with severe G6PD deficiency. Substituting etoposide for doxorubicin in DLBCL patients was associated with decreased survival.

Based on our data, standard regimens like ABVD or R-CHOP can be safely used in severely G6PD deficient patients, though larger multi-center studies would help in corroborating these findings. This study is of particular relevance in areas of the world with a high prevalence of severe G6PD deficiency like the Middle-East and Africa.