SUMMARY  

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
• Hemophagocytic lymphohistiocytosis (HLH) has been reported as an adverse event (AE) in the CARTITUDE-1 and CARTITUDE-4 studies.^1-4
• Monoclonal antibodies-targeting cytokines (for example, anti-interleukin [IL] 1 and/or anti-tumor necrosis factor alpha [TNF-α]) or therapy directed at reduction and elimination of chimeric antigen receptor (CAR)-T cells may be considered for patients who develop high grade cytokine release syndrome (CRS) and HLH, that remains severe or life-threatening following prior administration of tocilizumab and corticosteroids.⁵
• Clinical signs and symptoms of CRS may include but are not limited to fever (with or without rigors), chills, hypotension, hypoxia and elevated liver enzymes. Potentially life-threatening complications of CRS may include cardiac dysfunction, neurologic toxicity, and HLH. Patients who develop HLH have an increased risk of severe bleeding. Patients should be closely monitored for signs or symptoms of these events, including fever. Risk factors for severe CRS include high pre-infusion tumor burden, active infection and early onset of fever or persistent after 24 hours of symptomatic treatment.⁵
• Evaluation for HLH should be considered in patients with severe or unresponsive CRS. For patients with high pre-infusion tumor burden, early onset of fever, or persistent fever after 24 hours, early tocilizumab should be considered. The use of myeloid growth factors, particularly granulocyte macrophage-colony stimulating factor (GM-CSF), should be avoided during CRS. Consider reducing baseline burden of disease with bridging therapy prior to infusion with CARVYKTI in patients with high tumor burden.⁵
• CARTITUDE-1 (MMY2001) was a phase 1b/2 study that evaluated CARVYKTI in patients with relapsed/refractory multiple myeloma (RRMM) who had previously received a proteasome inhibitor (PI), an immunomodulatory drug, and an anti-CD38 antibody. The combined analysis from the phase 1b/2 portions of the CARTITUDE-1 study evaluated the safety and efficacy of CARVYKTI in 97 patients with RRMM.^1,2
  • In the CARTITUDE-1 study, the incidence of any grade HLH amongst the safety evaluated patients was 1%.⁵ 
    • CRS occurred in 95% of patients (n=92) with a median duration of 4 days (Interquartile range [IQR] 3-6). CRS resolved within 18 days of onset in all but
      1 patient who had a duration of CRS of 97 days, complicated by secondary HLH with a subsequent fatal outcome. The 1 death due to CRS/HLH was reported on
      day 99 post CARVYKTI infusion.^1,2,5
• CARTITUDE-4 (MMY3002) is a phase 3, randomized, open-label study evaluating the efficacy and safety of CARVYKTI versus standard care (physician's choice of pomalidomide, bortezomib, and dexamethasone [PVd] or DARZALEX FASPRO® [daratumumab and hyaluronidase], pomalidomide, and dexamethasone [DPd]) in adult patients with lenalidomide-refractory multiple myeloma (MM) after 1-3 prior line(s) of therapy (LOT). The safety of CARVYKTI was evaluated in 196 patients of the CARTITUDE-4 study.^3-5 
  • In the CARTITUDE-4 study, the incidence of any grade HLH amongst the safety evaluated patients was 2%.⁵ 

PRODUCT LABELING

• CARVYKTI (ciltacabtagene autoleucel) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.;http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/CARVYKTI-pi.pdf.
• DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf

background

Severe CRS can evolve into a presentation consistent with hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) that may require additional therapy. In these cases, laboratory testing may reveal high serum levels of ferritin, lactate dehydrogenase, soluble CD25, and cytokines (such as interferon gamma [IFN-ỵ] and IL-6), and low serum levels of fibrinogen. ^6,7

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 11 April 2025.