The New England Journal of MedicineIndolent CD4+ CAR T-Cell Lymphoma after Cilta-cel CAR T-Cell Therapy

Identification and Characterization of Indolent CD4+ CAR T-Cell Lymphoma Post-CAR T-Cell Therapy: Potential Mechanisms and Clinical Implications

A 71-year-old woman developed an indolent CD4+ cytotoxic chimeric antigen receptor (CAR) T-cell lymphoma involving the small intestine after receiving ciltacabtagene autoleucel (cilta-cel) CAR T-cell therapy for multiple myeloma. This case highlights the importance of recognizing secondary malignancies post-CAR T-cell therapy and stresses the need for thorough molecular and genomic analysis to understand the underlying mechanisms.

Key Points:

• Patient Background:
  • 71-year-old woman with an 8-year history of multiple myeloma.
  • Treated with cyclophosphamide–fludarabine lymphodepleting therapy followed by ciltacabtagene autoleucel (cilta-cel) CAR T-cell therapy targeting B-cell maturation antigen (BCMA).
  • Achieved complete response, negative for minimal residual disease (MRD).
• Symptom Onset:
  • Four months post-CAR T-cell therapy, the patient presented with progressively worsening nonbloody diarrhea and weight loss of 5.4 kg.
• Initial Laboratory and Diagnostic Findings:
  • Laboratory findings included abnormalities in serum bicarbonate, creatinine, and glomerular filtration rate.
  • Endoscopy revealed duodenal ulcerations initially interpreted as probable autoimmune enteropathy.
• Molecular and Histopathological Analysis:
  • Biopsy of duodenal ulcer showed small lymphocytes with minimal atypia, indicative of probable autoimmune enteropathy.
  • Further biopsy and molecular analysis confirmed CD4+ cytotoxic CAR T-cell lymphoma.
  • Whole-genome sequencing identified a single lentiviral insertion site within the SSU72 gene and numerous genetic alterations.
• Clinical Course and Treatment:
  • Initial treatment with intravenous methylprednisolone, oral budesonide, and IVIG showed improvement, but symptoms recurred after tapering glucocorticoids.
  • Continued treatment with mycophenolate mofetil was unsuccessful.
  • Transitioned to cyclophosphamide and teduglutide with ongoing total parenteral nutrition, showing mild improvement.
• Molecular Findings:
  • High levels of CAR T-cell chimeric fusions confirmed CD4+ CAR T-cell presence in the tumor.
  • Identified multiple somatic copy-number variations and genetic alterations related to cancer and immune system genes.
  • The lentiviral vector carrying the anti-BCMA CAR T-cell cassette was integrated into the positive strand of the first chromosome at position 1,556,938, affecting the SSU72 gene.
• Implications for Clinical Practice:
  • Recognition of secondary malignancies post-CAR T-cell therapy is crucial.
  • Thorough molecular and genomic analysis is essential for diagnosis and understanding the mechanisms of CAR T-cell-related lymphomagenesis.
  • Clinicians should be aware of the morphologic and immunophenotypic characteristics of CAR T-cell lymphoma when evaluating post-therapy complications.

In a recent study, researchers found that second primary malignancies were reported in 536 of 12,394 (4.3%) adverse events after CAR-T therapies in Adverse Event Reporting System (FAERS). Myeloid and T-cell neoplasms were disproportionately more frequent, with 208 reports of myelodysplasia and 106 reports of acute myeloid leukemias.

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