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Jump to Key Points Immunotherapy has improved the survival of patients with cancer; however, longer survival brings growing challenges in managing late and persistent treatment-related complications.
During the annual meeting of the German Society for Hematology and Medical Oncology (DGHO), Katharina Egger-Heid rich, MD, specialist in internal medicine, hematology, and oncology, and the head of internal medicine at the outpatient transition clinic at Dresden University Hospital in Dresden, Germany, highlighted the long-term risks associated with immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T-cell therapies and emphasized the need for tailored cancer survivorship care.
Although acute toxicities are increasingly well characterized, prospective data on long-term outcomes remain limited.
Checkpoint Inhibitors
Approximately one third of patients with cancer are eligible for ICI treatment, which is used across many tumor types, including as first-line therapy. Although acute adverse effects are well characterized, immune-related adverse events (irAEs) can develop later during treatment or persist after treatment ends.
- ICIs: chronic irAEs common (~50%); severe grade ≥3 in 10%-15%.
- Late endocrine irAEs: thyroiditis, hypophysitis, adrenal insufficiency; monitor long-term.
- ICI survivorship: watch CV, rheumatologic, endocrine symptoms; CKD risk ↑ with renal comorbidity.
- CAR T long-term: B-cell aplasia/CD4+ deficiency → hypogammaglobulinemia, infections, nonrelapse mortality.
- CAR T follow-up: secondary malignancies reported; fertility counseling + infection history essential.
Endocrine irAEs, including thyroiditis, hypophysitis, and adrenal insufficiency, are particularly likely to occur later. Chronic irAEs of any grade occur in approximately 50% of patients treated with ICIs, with severe events (grade ≥ 3) affecting 10%-15%.
Egger-Heidrich also highlighted an increased risk for chronic kidney disease, particularly among patients with comorbidities that already compromise kidney function.
Fertility after ICI treatment has not been extensively studied. Case reports have described ICI-associated orchitis, whereas preclinical data have suggested a potential risk for ovarian endocrinopathy. Patients of reproductive age should receive counseling regarding fertility preservation before treatment.
“An ICI survivorship care plan should pay particular attention to cardiovascular, rheumatologic, and endocrine symptoms,” Egger-Heidrich said.
CAR T Cells: Long-Term Effects on the Immune System
The first therapeutic use of CAR T cells occurred approximately 12 years ago, and their use continues to increase. Acute toxicities that develop within days or weeks are now well characterized and can be managed clinically. These include:
- Immune effector cell-associated neurotoxicity syndrome
- Cytokine release syndrome
- Infections
- Immune effector cell-associated hematotoxicity (ICAHT)
- Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome
Long-term complications include secondary immunodeficiencies caused by B-cell aplasia and CD4+ T-cell deficiency.
Hypogammaglobulinemia is the most common long-term consequence of CD19-directed CAR T-cell therapy. Infections are the leading cause of nonrelapse mortality.
ICAHT is a diagnosis of exclusion. The differential diagnosis includes disease recurrence with bone marrow infiltration, nutrient deficiencies, infections, drug-induced toxicity, treatment-associated myeloid neoplasms, and macrophage activation syndrome.
Treatment depends on severity, which is assessed based on the absolute neutrophil count. Management options include antiviral therapy, prophylaxis against Pneumocystis jirovecii pneumonia, granulocyte colony-stimulating factor, thrombopoietin receptor agonists, and immunosuppressive therapy in selected cases.
Allogeneic stem cell transplantation may be considered a last resort.
Secondary Malignancies, Fertility, and Follow-Up
A meta-analysis involving 5517 patients with multiple myeloma or lymphoma identified 326 cases of secondary malignancies after CAR T-cell therapy. Of these, 37% were hematologic neoplasms, primarily myelodysplastic syndrome; 27% were solid tumors, primarily genitourinary and gastrointestinal cancers; 16% were nonmelanoma skin cancers; and 20% were not further specified.
The median follow-up period was 21 months, and the reported incidence of secondary malignancies has increased with time since treatment. Egger-Heidrich noted that the analysis involved a heavily pretreated patient population.
Counseling on fertility preservation should also be offered before CAR T-cell therapy. Successful spontaneous pregnancies have been reported after treatment; however, prospective studies are needed to clarify its effects on fertility.
Survivorship care plans should account for previous treatments and include a detailed history of infection. Otherwise, follow-up care does not fundamentally differ from that for other cancer survivors. Egger-Heidrich also emphasized that inactivated vaccines are safe, although they may elicit a weaker immune response.
This story was translated from Coliquio, part of the Medscape Professional Network.
