What are the long-term adverse effects of stem cell therapy in patients with underlying medical conditions, such as autoimmune diseases or degenerative diseases?

Long-Term Adverse Effects of Stem Cell Therapy

The long-term adverse effects of stem cell therapy vary significantly by stem cell type, with autologous hematopoietic stem cell transplantation (AHSCT) carrying well-documented risks of secondary autoimmunity (7.7-18% incidence), infections, and endocrine complications, while mesenchymal stem cell therapy appears relatively safe in small trials but lacks adequate long-term safety data.

Type-Specific Long-Term Adverse Effects

Autologous Hematopoietic Stem Cell Transplantation (AHSCT)

Secondary Autoimmune Diseases:

• High-intensity myeloablative conditioning regimens with busulfan carry an 18% overall incidence of secondary autoimmunity across multiple studies 1
• Intermediate-intensity non-myeloablative regimens show lower incidence (7.7% overall), though alemtuzumab-containing regimens reach 14% incidence 1
• Autoimmune thyroiditis occurs in 11% of patients within the first 3 years after AHSCT with BEAM-ATG or cyclophosphamide-ATG regimens—nearly sixfold higher than standard disease-modifying therapies 1
• Immune thrombocytopenic purpura (ITP) occurs in 11.5% with alemtuzumab-containing regimens 1
• Less common secondary autoimmune diseases include autoimmune hemolytic anemia, acquired hemophilia, antiphospholipid syndrome, and myasthenia gravis 1

Infectious Complications:

• Risk of infections (mainly pneumonia and VZV reactivation) is highest during the first 2 years after AHSCT, though systematic evidence is lacking 1
• Standard prophylaxis includes coverage for invasive fungal infections for 3-4 months, and herpesvirus and pneumocystis infection for 6 months 1
• CMV and EBV reactivation require monitoring with standardized PCR assays, particularly during days 15-60 post-transplant 1

Malignancy Risk:

• At 10 years post-AHSCT, predictive cumulative incidence of malignancies is 3.5% in autoimmune disease patients 1
• No current evidence suggests increased lifetime malignancy risk in non-malignant (autoimmune) primary disease settings, contrasting with oncology field concerns 1
• Low event numbers and previous immunosuppressive treatment exposure prevent accurate risk estimation 1

Endocrine and Metabolic Complications:

• Endocrine or bone complications occur in 20.3% of patients at 10 years 1
• Cardiac complications occur in 13.1% at 10 years 1

Fertility Effects:

• Fertility impairment is a recognized delayed adverse event, though specific incidence data are sparse 1

Mesenchymal Stem Cell (MSC) Therapy

Limited Long-Term Safety Data:

• The vast majority of small-sized clinical trials with MSC in regenerative medicine have not reported major health concerns, suggesting relative safety 2
• However, serious adverse events have been reported in some clinical trials, emphasizing the need for additional knowledge regarding biological mechanisms and long-term safety 2
• Potential long-term adverse effects on the immune system remain unknown 1

Theoretical Risks:

• MSCs possess the ability to promote tumor growth and metastasis, though clinical evidence is limited 3
• Small patient numbers and lack of adequate controls in existing studies prevent definitive conclusions about long-term benefits or harms 1

Pluripotent Stem Cells (Embryonic Stem Cells and iPSCs)

High Theoretical Risk Profile:

• Based on characteristics of unlimited self-renewal and high proliferation rate, risks associated with pluripotent stem cells (particularly tumor formation) are considered high or potentially unacceptable 2
• Currently no clinical experience exists with pluripotent stem cells in humans 2
• Undesired differentiation and malignant transformation represent major safety concerns 3

Critical Monitoring Recommendations

For AHSCT Recipients:

• Monitor for secondary autoimmune diseases, particularly thyroiditis and ITP, with heightened vigilance in patients who received alemtuzumab before AHSCT 1
• Perform immune monitoring for T cell and B cell subsets and immunoglobulin electrophoresis every 3 months in the first year, then annually 1
• Collect long-term survival data using standardized surveillance tools to capture late adverse events, particularly late infections and malignancies 1
• Conduct long-term objective neurological assessments and MRI data collection systematically 1

For All Stem Cell Therapy Recipients:

• Systematic collection of patient-reported outcomes and objective measures is needed to adequately assess long-term complications 1

Important Caveats

Conditioning Regimen Matters:

• BEAM regimens show pooled rates of secondary autoimmune diseases <1%, though this may reflect under-reporting rather than true safety 1
• Higher-intensity conditioning correlates with higher secondary autoimmunity risk 1

Lack of Adequate Evidence:

• Data on frequency of late adverse events after AHSCT for autoimmune diseases and their relationship to treatment are sparse 1
• Limited information exists on cardiovascular and bone mineral disease complications 1
• Most MSC studies involve small numbers without control groups, preventing accurate safety assessment 1

Potential Mitigation Strategies:

• Post-transplantation B cell depletion with rituximab may prevent secondary autoimmunity and warrants further investigation 1