What is the best salvage therapy option for a patient with relapsed or refractory non-Hodgkin lymphoma (NHL) who has undergone a polar CHP (cyclophosphamide, hydroxydaunorubicin, and prednisone) chemotherapy regimen, between R-DHAP (rituximab, dexamethasone, cisplatin, and cytarabine), R-ICE (rituximab, ifosfamide, carboplatin, and etoposide), and EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin)?

Salvage Therapy for Relapsed/Refractory Non-Hodgkin Lymphoma

All three platinum-based regimens (R-DHAP, R-ICE, and R-EPOCH) are equally effective for salvage therapy in relapsed/refractory NHL, with no superiority demonstrated between them, so the choice should be based on institutional experience and patient-specific toxicity considerations. 1

Evidence Supporting Equivalence

The most recent ESMO guidelines explicitly state that comparative trials between these salvage regimens are lacking, and any of the published platinum-based salvage regimens such as R-DHAP, R-ESHAP, R-EPOCH, or R-ICE may be adequate for patients eligible for transplantation. 1 A head-to-head comparison between R-DHAP and R-ICE showed no differences in outcomes, confirming their equivalence. 1

Key Decision Points

Patient Eligibility for High-Dose Therapy

• For transplant-eligible patients (adequate performance status, no major organ dysfunction, age <65 years): Use any platinum-based salvage regimen followed by high-dose chemotherapy with autologous stem cell transplantation. 1, 2
• For transplant-ineligible patients: Use the same platinum-based regimens or gemcitabine-based alternatives, potentially combined with involved-field radiotherapy. 1

Rituximab Considerations

• Add rituximab to salvage therapy if the patient was not previously exposed to rituximab in first-line treatment, as this significantly improves outcomes. 1
• Rituximab's benefit is uncertain in patients who relapsed after rituximab-containing first-line therapy, though it is commonly used in practice. 1
• Do not add rituximab if the patient is refractory to a previous rituximab-containing regimen. 1

Regimen-Specific Toxicity Profiles

R-DHAP (Rituximab, Dexamethasone, Cisplatin, Cytarabine)

• Primary toxicities: Nephrotoxicity from cisplatin, requiring adequate hydration and renal monitoring. 3, 4
• Hematologic toxicity: Grade 4 leukocytopenia (43% of courses) and thrombocytopenia (48% of courses), with mean durations of 1.1 and 1.4 days respectively. 3
• Stem cell mobilization: Effective for peripheral blood stem cell collection, with peak CD34+ cell counts on day 12 after G-CSF support. 3
• Contraindication: Avoid in patients with pre-existing renal insufficiency. 4

R-ICE (Rituximab, Ifosfamide, Carboplatin, Etoposide)

• Primary toxicities: Myelosuppression and potential hemorrhagic cystitis from ifosfamide (requires mesna prophylaxis). 1
• Equivalence to R-DHAP: No survival differences demonstrated in direct comparison. 1

R-EPOCH (Rituximab, Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin)

• Primary toxicities: Cardiotoxicity from doxorubicin (particularly relevant if patient received anthracyclines in first-line therapy), peripheral neuropathy from vincristine. 1
• Cumulative anthracycline consideration: Document total anthracycline dose from first-line therapy; if additional anthracyclines are planned, perform echocardiography or MUGA scan to quantify ejection fraction. 1, 2, 5

Alternative Regimen: R-DHAX (Oxaliplatin Substitution)

Consider R-DHAX (substituting oxaliplatin for cisplatin) in patients with renal insufficiency or those at high risk for nephrotoxicity. 6, 7, 4

• Efficacy: Overall response rate of 75% with complete response rate of 57%, comparable to R-DHAP. 4
• Toxicity advantage: No renal toxicity or degradation of pre-existing renal insufficiency observed, making it suitable for elderly patients and those with baseline renal dysfunction. 6, 4
• Neurologic toxicity: Grade I/II sensory or motor neuropathy (mainly transient), with 3 cases of persistent motor neuropathy in patients previously exposed to vincristine. 4
• Hematologic toxicity: Similar to R-DHAP, with grade III/IV neutropenia and thrombocytopenia requiring close monitoring. 4

Common Pitfalls to Avoid

• Do not delay referral for transplant evaluation: Patients should be referred to a transplant center as soon as they fulfill poor-risk criteria to avoid development of further treatment resistance or disease transformation. 1
• Mandatory biopsy before salvage therapy: Histological verification is required, especially for relapses >12 months after initial diagnosis, to confirm relapse and exclude transformation. 1, 2, 5
• Avoid routine rituximab in rituximab-refractory disease: Adding rituximab to salvage therapy in patients who progressed during or immediately after rituximab-containing therapy is unlikely to provide benefit. 1
• Monitor for tumor lysis syndrome: In patients with high tumor burden, implement prophylactic measures including hydration, allopurinol or rasburicase, and electrolyte monitoring. 1