1. Prophylaxis Regimens

Prophylactic immunosuppression is critical to reduce the incidence and severity of GVHD by targeting the activation and proliferation of donor T-cells. The standard of care involves combining a calcineurin inhibitor (CNI) with an antiproliferative agent, typically methotrexate or mycophenolate mofetil (MMF).

2. First-Line Treatment: Systemic Corticosteroids

Systemic corticosteroids are the undisputed cornerstone for treating newly diagnosed acute GVHD (grades II–IV). They exert broad immunosuppressive effects by inhibiting T-cell proliferation and suppressing the inflammatory cytokine cascade.

Indications and Dosing

• Grade II GVHD: Initiate prednisone 1 mg/kg/day (or equivalent) for persistent symptoms (e.g., Stage 2 skin, Stage 1-2 GI/liver) beyond 3 days.
• Grades III–IV GVHD: Immediately start high-dose prednisone 2 mg/kg/day (or equivalent).

Tapering and Monitoring

Once a clinical response is achieved (typically within 5–7 days), a slow taper is initiated to prevent disease flare. A common strategy is to decrease the dose by approximately 10% every 5–7 days, aiming for completion over 8–12 weeks. Patients with multi-organ involvement may require a more prolonged taper. Key monitoring includes daily blood glucose, blood pressure, and implementing prophylaxis for Pneumocystis jirovecii (PJP) and fungal infections.

3. Second-Line and Salvage Therapies

Steroid-refractory (SR) GVHD, defined as progression after 3 days or no improvement after 7 days of high-dose steroids, carries a poor prognosis. Second-line therapy involves more targeted immunomodulation, with agent selection depending on whether the GVHD is acute or chronic.

4. PK/PD Considerations in the Critically Ill

Critical illness profoundly alters drug pharmacokinetics (PK) and pharmacodynamics (PD). These changes are particularly relevant for narrow therapeutic index drugs like CNIs, necessitating careful dose adjustments and monitoring.

• Volume of Distribution (Vd): Capillary leak and fluid resuscitation increase the Vd, potentially lowering peak drug concentrations.
• Protein Binding: Hypoalbuminemia, common in critical illness, increases the free (active) fraction of highly protein-bound drugs like cyclosporine, raising the risk of toxicity even with “therapeutic” total drug levels.
• Hepatic/Renal Dysfunction: Organ failure impairs drug metabolism and clearance. CNI doses should be empirically reduced by 30–50% in hepatic impairment and then titrated to trough levels.
• Drug Delivery: In patients with severe GI GVHD, shock, or ileus, IV formulations are essential to ensure reliable absorption. Transition back to PO formulations as soon as clinically feasible.

5. Therapeutic Drug Monitoring (TDM)

TDM is mandatory for CNIs to balance efficacy and toxicity. Accurate sampling and interpretation are critical for patient safety.

6. Pharmacoeconomics and Cost Considerations

The introduction of targeted therapies for SR-GVHD has significantly improved outcomes but also introduced substantial costs. Ruxolitinib and ibrutinib can cost over $17,000–$25,000 per month. When making treatment decisions, it is important to weigh this high acquisition cost against potential savings from reduced length of stay, fewer complications, and improved quality of life. For example, using MMF over methotrexate in prophylaxis may increase upfront drug cost but can reduce overall costs by mitigating severe mucositis and its associated need for parenteral nutrition and prolonged hospitalization.

7. Guideline Controversies and Decision Points

While guidelines provide a strong framework, several areas of GVHD management lack uniform consensus, requiring multidisciplinary input and clinical judgment. Key debates include the optimal timing for initiating second-line therapy (e.g., waiting 5-7 days vs. 10-14 days for steroid response) and the ideal intensity of immunosuppression, which must constantly be balanced against the desired graft-versus-tumor effect and the risk of life-threatening infection.

8. Integration with Supportive Care

Pharmacotherapy for GVHD does not exist in a vacuum. It must be integrated with aggressive supportive care to manage complications of both the disease and its treatment.

• Antimicrobial Prophylaxis: Essential due to profound immunosuppression. This includes mold-active azoles (or echinocandins), trimethoprim-sulfamethoxazole for PJP, and antiviral agents with preemptive CMV monitoring.
• Nutrition: Early initiation of enteral nutrition is preferred. Total parenteral nutrition (TPN) is reserved for patients with severe mucositis or GI GVHD who cannot tolerate enteral feeds.
• Mobility: Early engagement with physical and occupational therapy is vital to prevent ICU-acquired weakness and deconditioning.