What is the recommended washout period for daratumumab (Darzalex) before chimeric antigen receptor T‑cell (CAR‑T) therapy?

Washout Period for Daratumumab (Darzalex) Before CAR T-Cell Therapy

The provided guidelines do not specify a washout period for daratumumab before CAR T-cell therapy; however, based on the pharmacokinetics of monoclonal antibodies and general principles for anti-CD38 therapy, a minimum washout of 3-4 weeks is recommended to allow clearance and avoid potential interference with CAR T-cell manufacturing and function.

Critical Context: Why This Matters

The absence of daratumumab-specific guidance in the 2022 EBMT/EHA CAR T-cell management guidelines 1 is notable, as these comprehensive recommendations address washout periods for multiple therapy types but do not include anti-CD38 monoclonal antibodies. This creates a clinical challenge that requires extrapolation from related evidence.

Recommended Approach Based on Available Evidence

Before Leukapheresis (T-Cell Collection)

• Apply the high-dose chemotherapy washout principle: The EBMT/EHA guidelines recommend 3-4 weeks washout for high-dose chemotherapy before leukapheresis, with recovery from cytopenias required 1
• Consider daratumumab's mechanism: As a monoclonal antibody that depletes CD38+ cells (including some T-cell subsets), daratumumab may affect the quality and quantity of collected T-cells for CAR T manufacturing
• Ensure adequate lymphocyte recovery: The guidelines specify an absolute lymphocyte count ≥0.2 × 10⁹/L is recommended before leukapheresis 1

Before Lymphodepletion/CAR T Infusion

• Follow bridging therapy principles: For therapies given between leukapheresis and CAR T infusion, the EBMT/EHA recommends 3-4 weeks washout for high-dose chemotherapy and 3 days for short-acting cytotoxic drugs 1
• Account for daratumumab's half-life: Monoclonal antibodies typically have elimination half-lives of 2-3 weeks, suggesting 3-4 weeks allows for substantial clearance
• Avoid potential CAR T interference: Daratumumab's anti-CD38 activity could theoretically interfere with CAR T-cell expansion if CD38 is expressed on activated T-cells

Special Considerations for Multiple Myeloma Patients

BCMA-Targeted CAR T-Cell Therapy

• Daratumumab does not target BCMA: Unlike CD38, BCMA is the primary target for most myeloma CAR T products, so direct target interference is not a concern 2
• Prior daratumumab exposure is common: Many myeloma patients receiving CAR T-cell therapy have received daratumumab as part of prior treatment regimens 3, 4, 5
• Manufacturing considerations: Ensure T-cells collected for CAR T manufacturing are not significantly depleted or functionally impaired by recent daratumumab exposure

Practical Algorithm

Step 1: Determine timing of last daratumumab dose relative to planned leukapheresis

Step 2: If daratumumab was given within 4 weeks of planned leukapheresis:

• Check absolute lymphocyte count
• If ALC <0.2 × 10⁹/L, delay leukapheresis until recovery 1
• If ALC adequate, proceed but document for manufacturing team

Step 3: For bridging therapy between leukapheresis and CAR T infusion:

• Avoid daratumumab during this period if possible
• If daratumumab must be used, allow minimum 3-4 weeks washout before lymphodepletion 1

Step 4: Ensure coagulation parameters and complete blood counts are normalized before proceeding with CAR T infusion 6

Common Pitfalls to Avoid

• Don't assume all monoclonal antibodies have the same washout requirements: While rituximab and daratumumab are both monoclonal antibodies, their targets and mechanisms differ
• Don't overlook lymphocyte recovery: Focus not just on time elapsed, but on functional recovery of lymphocyte counts before leukapheresis 1
• Don't restart daratumumab too early post-CAR T: Wait until cytokine release syndrome has resolved and coagulation parameters normalized, typically 7-14 days post-infusion 6

When Guidelines Are Silent: Clinical Judgment

Given the lack of specific guidance, the conservative approach of 3-4 weeks washout aligns with recommendations for other intensive therapies and allows for:

• Adequate drug clearance based on antibody pharmacokinetics
• Recovery of lymphocyte populations
• Minimization of potential interference with CAR T-cell function
• Reduction of cumulative toxicity risk

This recommendation prioritizes patient safety and CAR T-cell therapy success in the absence of definitive evidence-based guidance for this specific clinical scenario.