Is there harm in giving steroids for persistent fever in new acute myeloid leukemia (AML) patients prior to initiating treatment with Vidaza (azacitidine) and Venetoclax (venetoclax)?

Steroid Use for Persistent Fever in New AML Prior to Venetoclax-Azacitidine Treatment

Steroids should generally be avoided for fever management in new AML patients prior to initiating venetoclax-azacitidine, as fever in this setting most likely represents infection requiring empirical antibiotics rather than symptomatic treatment, and steroids may mask infection or worsen immunosuppression without addressing the underlying cause.

Primary Management Approach for Persistent Fever

Standard of Care for Febrile Neutropenia

• Empirical broad-spectrum antibiotic therapy is mandatory for febrile patients with neutropenia in AML 1
• The European Conference on Infections in Leukemia (ECIL) guidelines specifically recommend standard empirical antibiotic approaches for neutropenic fever in patients receiving venetoclax-azacitidine combinations 1
• Fever persisting beyond 24 hours despite antipyretics strongly suggests an infectious etiology requiring antimicrobial escalation, not immunosuppression 1

Infection Risk with Venetoclax-Azacitidine

• Febrile neutropenia occurs in 30-61% of patients receiving venetoclax combined with hypomethylating agents 1
• Infections occurred in 84% of patients in the azacitidine-venetoclax group versus 67% in azacitidine monotherapy 1
• A real-world study found 72.8% of AML patients developed infections during the first cycle of venetoclax-HMA therapy, with documented infections in 71.2% of those cases 2
• The most common pathogens include Candida albicans, Klebsiella pneumoniae, and Pseudomonas aeruginosa 2

Why Steroids Are Problematic

Masking of Infection

• Steroids suppress fever and inflammatory responses, potentially masking progression of serious bacterial, fungal, or viral infections that are highly prevalent in this population 1
• In AML patients with persistent fever, sepsis is a more common cause of jaundice and systemic symptoms than drug effects, occurring in 22% of hospitalized patients 3

Immunosuppression Concerns

• Venetoclax causes neutropenia as its primary immune impact, with no additional specific immunosuppressive effects beyond myelosuppression 1
• Adding corticosteroids would compound immunosuppression in already neutropenic patients at high infection risk 1
• The combination of venetoclax-azacitidine already carries substantial infection risk without additional immunosuppressive agents 1, 2

Appropriate Fever Management Algorithm

Immediate Actions (Within Hours)

1. Obtain blood cultures (peripheral and central line if present) before initiating antibiotics 1
2. Start empirical broad-spectrum antibiotics immediately - do not delay for culture results 1
3. Perform comprehensive infectious workup: chest imaging, urinalysis/culture, site-specific cultures based on symptoms 1

If Fever Persists Beyond 24-48 Hours

1. Reassess antibiotic coverage - consider escalation to cover resistant organisms or addition of antifungal therapy 1
2. Consider antifungal prophylaxis or empirical therapy, particularly if neutropenia is profound or prolonged 1
3. Review all medications for drug-drug interactions, especially CYP3A4 inhibitors that may affect venetoclax levels 1, 3

Specific Considerations Before Starting Venetoclax-Azacitidine

• Documented active infection is a valid reason to temporarily delay venetoclax-azacitidine initiation 1
• Recent evidence suggests delaying venetoclax-based therapy up to 10 days in newly diagnosed AML does not impact overall survival (7.7 vs 9.6 months, P=0.42), provided close clinical monitoring is performed 4
• Anti-infective agents should be administered during this period 1

Limited Role for Steroids in This Context

The Only Appropriate Steroid Use

• Steroids may be considered for tumor flare reactions specifically related to lenalidomide-based regimens in CLL/lymphoma, not for AML treatment with venetoclax-azacitidine 1
• This is not applicable to your clinical scenario of fever management in AML

What Steroids Do NOT Address

• Steroids do not treat the underlying infection causing fever 1
• Steroids do not reduce mortality from febrile neutropenia 1
• Symptomatic fever reduction with antipyretics and cooling measures is already being attempted without success, indicating a need for antimicrobial escalation, not immunosuppression 1

Critical Pitfalls to Avoid

• Do not use steroids as a substitute for appropriate antimicrobial therapy in neutropenic fever 1
• Do not delay empirical antibiotics while pursuing diagnostic workup 1
• Do not overlook drug-drug interactions - ensure proper venetoclax dose adjustments if strong CYP3A4 inhibitors (azole antifungals, macrolides) are used 1, 5
• Consider dose interruptions of venetoclax to allow hematologic recovery if severe neutropenia persists with good disease response 1

Prophylaxis Recommendations for Future Cycles

• Consider antibacterial and antifungal prophylaxis when hypomethylating agents are combined with venetoclax 1
• Standard prophylaxis as for intensive AML chemotherapy is recommended 1
• Fluoroquinolones decrease gram-negative infections in patients with expected prolonged profound granulocytopenia 1