Gray Zone Lymphoma Treatment
For gray zone lymphoma, treat with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone) or dose-adjusted EPOCH-R as frontline therapy, with consolidative radiotherapy for localized or bulky disease, and reserve autologous stem cell transplantation for relapsed/refractory cases.
Frontline Treatment Selection
The optimal treatment for gray zone lymphoma (GZL) requires DLBCL-directed regimens rather than Hodgkin lymphoma protocols, as outcomes are markedly superior with this approach 1, 2.
Primary treatment options include:
- R-CHOP (rituximab 375 mg/m² plus cyclophosphamide, doxorubicin, vincristine, prednisone) administered every 21 days for 6-8 cycles 3, 1, 2
- Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab) as an alternative regimen 1, 4
The evidence strongly favors DLBCL-directed therapy over Hodgkin-directed regimens. Patients treated with ABVD±R had markedly inferior 2-year progression-free survival (22% versus 52%, P=0.03) compared with DLBCL-directed therapy, with this difference persisting on multivariable analysis (hazard ratio 1.88, P=0.04) 2.
Rituximab is essential: The addition of rituximab significantly improves outcomes, with multivariable analysis demonstrating improved progression-free survival (hazard ratio 0.35,95% CI 0.18-0.69, P=0.002) 2.
Consolidative Radiotherapy
Add consolidative radiotherapy for:
- Localized disease (stage I-II) 1
- Bulky disease (>10 cm mass) 1
- Mediastinal involvement with residual disease 1
Mediastinal disease occurs in 69% of confirmed GZL cases, making radiotherapy consideration particularly relevant 5.
Special Clinical Scenarios
For patients with severe organ impairment at presentation:
Brentuximab vedotin (BV) monotherapy can serve as a bridge to combination chemotherapy in CD30-positive GZL with baseline organ dysfunction 4. CD30 expression occurs in 92% of confirmed GZL cases 5. After organ function improvement with BV, transition to DA-EPOCH-R or R-CHOP 4.
Performance status and stage are critical prognostic factors on multivariable analysis, with hypoalbuminemia also predicting inferior outcomes (3-year PFS 12% versus 64%, P=0.01) 5, 2.
Relapsed/Refractory Disease Management
For relapsed or refractory GZL:
- Salvage chemotherapy followed by consolidative autologous hematopoietic stem cell transplantation (HSCT) 1, 6
- Relapsed/refractory GZL patients are salvaged fairly successfully with HSCT despite high initial relapse rates 1
The 2-year progression-free survival for all GZL patients is only 40%, with 33% having primary refractory disease, underscoring the aggressive nature requiring intensive salvage approaches 2.
Disease Characteristics Requiring Recognition
Clinical presentation patterns:
- 43% present with mediastinal disease (MGZL) 2
- 57% present with non-mediastinal systemic disease (NMGZL) 2
- Non-mediastinal patients are older (median 50 versus 37 years), more often have bone marrow involvement (19% versus 0%), advanced stage (81% versus 13%), but less bulk (8% versus 44%) 2
Diagnostic features:
- Universal B-cell derivation (PAX5+ 100%, CD20+ 83%) 5
- Frequent CD30 expression (92%) 5
- Rare EBV positivity (4%) 5
- Tumor cell-rich morphology is critical for diagnosis 5
Critical Pitfalls to Avoid
Do not use ABVD-based regimens: Despite GZL having features intermediate between Hodgkin lymphoma and DLBCL, Hodgkin-directed therapy produces inferior outcomes 2.
Do not omit rituximab: Even though GZL shares features with classical Hodgkin lymphoma (which is CD20-negative), the B-cell derivation and CD20 expression in 83% of cases makes rituximab essential 5, 2.
Accurate diagnosis is challenging: Only 38% of cases initially diagnosed as GZL were confirmed on expert central pathology review, with 62% reclassified (most commonly to nodular sclerosis Hodgkin lymphoma grade 2) 5. Involvement by expert hematopathologists is mandatory 1.