Can R-ICE (Rituximab, Ifosfamide, Carboplatin, Etoposide) chemotherapy cause fever?

Can R-ICE Chemotherapy Cause Fever?

Yes, R-ICE chemotherapy can cause fever, primarily through two mechanisms: febrile neutropenia (a direct consequence of myelosuppression) and infusion-related reactions from rituximab.

Fever as a Direct Toxicity of R-ICE Components

Febrile Neutropenia Risk

R-ICE (rituximab, ifosfamide, carboplatin, etoposide) is classified as a high-risk regimen for febrile neutropenia, with an expected incidence exceeding 20%. 1

• The NCCN explicitly lists both ICE and RICE regimens among chemotherapy protocols with high febrile neutropenia risk (>20%) for diffuse large B-cell lymphoma and peripheral T-cell lymphomas in second-line or salvage settings 1
• Febrile neutropenia is defined as temperature ≥38°C with neutrophil count <500/mcL or <1000/mcL with predicted decline to 500/mcL over 48 hours 1

Individual Agent Contributions

Ifosfamide specifically causes fever in approximately 1% of patients as a direct adverse effect, independent of neutropenia. 2

• Fever is listed as a distinct adverse reaction in the FDA label for ifosfamide, occurring in 1% of patients 2
• Myelosuppression from ifosfamide is dose-related and dose-limiting, with leukopenia expected in 50% of patients at standard doses 2

Etoposide contributes to myelosuppression with granulocyte nadirs occurring 7-14 days after administration, creating the neutropenic window during which fever and infection commonly develop. 3

• Fever and infection are specifically reported in neutropenic patients receiving etoposide 3
• Death associated with myelosuppression has been documented with etoposide 3

Clinical Evidence from R-ICE Studies

Observed Febrile Neutropenia Rates

In prospective clinical trials, febrile neutropenia occurred in 8% of patients receiving modified R-ICE regimens, though this likely underestimates true incidence given the outpatient nature of some protocols. 4

• A phase I/II trial of bendamustine-based salvage therapy (replacing ifosfamide) reported grade ≥3 febrile neutropenia in 8% of patients 4
• Grade IV neutropenia was documented in 53% of patients receiving outpatient ICE therapy 5
• In Japanese patients, 80% experienced grade 4 neutropenia after the first ICE cycle 6

Pediatric Experience

Rituximab infusion-related reactions causing fever were frequent but manageable in pediatric patients receiving R-ICE. 7

• Toxicities related to rituximab infusions were common in children with relapsed B-cell lymphomas 7
• These reactions typically manifested as fever, chills, and other infusion symptoms 7

Prophylaxis and Management Implications

Growth Factor Support

Prophylactic granulocyte colony-stimulating factor (G-CSF) is recommended for R-ICE given its high febrile neutropenia risk (>20%). 1

• G-CSF should be administered starting day +5 after chemotherapy 5
• Primary prophylaxis with G-CSF can reduce febrile neutropenia incidence by approximately 50% 1

Empirical Antibiotic Therapy

Empirical broad-spectrum antibiotics are warranted for any patient receiving R-ICE who develops fever, especially if neutropenic. 1

• Sepsis screening and empirical antibiotics are recommended for febrile neutropenic patients 1
• Infection workup should include blood and urine cultures, and chest radiograph if fever is present 1

Critical Pitfalls to Avoid

Do not attribute all fever in R-ICE patients to cytokine release syndrome or CAR T-cell therapy complications—these guidelines apply to different immunotherapy contexts. 1, 8

• The CRS grading systems and tocilizumab-based management protocols cited in several guidelines 1, 8 are specific to CAR T-cell therapy and checkpoint inhibitors, not conventional chemotherapy like R-ICE
• Fever in R-ICE patients should prompt evaluation for neutropenic fever and infection, not CRS management

Do not delay empirical antibiotics while awaiting culture results in neutropenic patients with fever—infectious mortality risk necessitates immediate treatment. 1, 9

• Fever may be the first and only manifestation of infection in neutropenic patients 1
• Standard practice requires broad-spectrum antibiotics for all patients with fever and neutropenia 1

Monitor for prolonged myelosuppression, as one patient in clinical trials required removal from study due to this complication. 7