What is the R-ICE (Rituximab, Ifosfamide, Carboplatin, Etoposide) protocol for relapsed or refractory non-Hodgkin lymphoma?

R-ICE Protocol for Relapsed or Refractory Non-Hodgkin Lymphoma

R-ICE (Rituximab, Ifosfamide, Carboplatin, Etoposide) is a highly effective salvage chemotherapy regimen for transplant-eligible patients with relapsed or refractory non-Hodgkin lymphoma, particularly diffuse large B-cell lymphoma, with an overall response rate of approximately 85-89%. 1

Components and Administration

The R-ICE regimen consists of:

• Rituximab: 375 mg/m² IV on day 1
• Ifosfamide: 5000 mg/m² IV, divided into three equal doses given over days 1-3
• Carboplatin: Dosed at AUC 5 IV on day 1
• Etoposide: 100 mg/m² IV daily for 3 days (days 1-3)
• G-CSF (Filgrastim): 5 μg/kg subcutaneously daily starting from day 5

The regimen is typically administered every 21 days as an outpatient treatment 1.

Clinical Applications

R-ICE is primarily used in:

1. Second-line therapy for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are candidates for high-dose therapy with autologous stem cell rescue 2
2. Stem cell mobilization prior to autologous stem cell transplantation 1
3. Salvage therapy for other aggressive non-Hodgkin lymphomas including follicular lymphoma (often with rituximab) 3

Efficacy

• Overall response rates of 87-89% have been reported 3, 1
• Complete response rates of approximately 29-37% 3, 1
• Partial response rates of approximately 50-60% 3, 1
• For DLBCL specifically, overall response rate of 85% (36% CR, 49% PR) 1

Stem Cell Mobilization Capability

R-ICE is effective for peripheral blood stem cell mobilization:

• Median time to PBSC harvest: 14 days
• Median CD34+ cell yield: 4.8-5.2 × 10⁶ cells/kg
• Mobilization failure rate: approximately 7% 1

Toxicity Profile

Hematological Toxicities

• Grade III/IV thrombocytopenia: 71% of patients
• Grade III/IV neutropenia: 72% of patients 1
• Febrile neutropenia risk >20% (classified as high-risk regimen) 2

Non-Hematological Toxicities

• CNS toxicity (grade 1/2): uncommon
• Cardiac toxicity: rare
• Renal impairment: rare
• Hepatotoxicity: rare 1

Important Considerations

1. Patient Selection: Best suited for transplant-eligible patients (generally age <65 years) with good performance status and no major organ dysfunction 2

2. Pre-Treatment Assessment:

   • Evaluate cumulative anthracycline exposure from prior therapy
   • Assess cardiac function (MUGA or echocardiography) if previous anthracycline exposure
   • Determine International Prognostic Index (IPI) score
   • Complete staging workup including CT scans and bone marrow assessment 2

3. Supportive Care:

   • G-CSF support is essential to manage neutropenia
   • Prophylactic antibiotics may be considered
   • Adequate hydration and mesna administration with ifosfamide to prevent hemorrhagic cystitis

Treatment Algorithm

1. For transplant-eligible patients (age <65, good performance status):

   • Administer 2-3 cycles of R-ICE
   • Assess response after 2 cycles
   • If responsive, proceed to stem cell collection and high-dose therapy with autologous stem cell transplantation 2

2. For non-transplant candidates:

   • R-ICE can still be used but with dose modifications as needed
   • Consider alternative regimens with lower toxicity profiles
   • May combine with involved field radiotherapy 2

Monitoring and Response Assessment

• Complete blood counts before each cycle
• Radiological assessment after 2-4 cycles of therapy (before stem cell collection)
• Final response assessment after completion of all planned therapy 2

Clinical Pearls and Pitfalls

• Rituximab addition: May not be beneficial in patients who were refractory to a previous rituximab-containing regimen 2
• Hydration: Adequate hydration is critical when administering ifosfamide to prevent nephrotoxicity
• Outpatient administration: Despite its intensity, R-ICE can be safely administered in the outpatient setting with proper monitoring 3, 1
• Stem cell collection timing: Optimal timing for stem cell collection is typically around day 14 of the cycle 1

R-ICE represents one of several effective salvage regimens for relapsed/refractory non-Hodgkin lymphoma, with comparable efficacy to other regimens such as R-DHAP, R-ESHAP, and R-GDP, though no head-to-head comparative trials have established superiority of any one regimen 2.