Immunomodulating Agent-associated Lymphoproliferative Disorders
Tariq Muzzafar, MBBS
Key Facts
Etiology/Pathogenesis
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Risk factors for IA-LPDs
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Type of immunosuppressive drug
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Duration of drug therapy
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Underlying disease type and disease activity
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Patient genetic background
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EBV plays role in subset of cases
Clinical Issues
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Presentation and therapy similar to corresponding LPDs in immunocompetent patients
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Methotrexate-associated LPD
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Partial regression after drug withdrawal in subset of cases, especially if EBV(+)
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TNF-α inhibitors
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Regression after drug withdrawal is uncommon
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HSTCL in Crohn disease
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Fatal in most patients
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Microscopic Pathology
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Many lymphoma types described in patients on immunomodulator therapy
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Analogous to other immunodeficiency states; most common are
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Diffuse large B-cell lymphoma
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Classical Hodgkin lymphoma; Hodgkin-like LPD
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Polymorphic/lymphoplasmacytic LPD
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Hepatosplenic T-cell lymphoma
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Ancillary Tests
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Immunophenotype similar to corresponding LPDs in immunocompetent patients
Diagnostic Checklist
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Knowledge of drug therapy essential for diagnosis
TERMINOLOGY
Abbreviations
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Immunomodulating agent-associated lymphoproliferative disorders (IA-LPD)
Definitions
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LPDs in patients treated with immunosuppressive drugs, usually for autoimmune diseases
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LPDs arising in setting of transplantation are excluded
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ETIOLOGY/PATHOGENESIS
Risk Factors for IA-LPD
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Type of immunosuppressive drug
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Methotrexate (MTX), tumor necrosis factor (TNF)-α antagonists, etc.
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Duration of drug therapy
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Underlying disease type and disease activity
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Rheumatoid arthritis (RA) appears to have highest risk
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Patient genetic background
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Difficult to tease out relative contributions of these factors
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Risk factors point to potential pathogenesis
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Immunosenescence and Lymphomagenesis in RA
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RA patients with lymphoma have mean age of 70 years (range 32-91)
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Increased age is correlated with immunosenescence
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B-cell immune dysregulation in RA could drive B cell expansion
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B-cell autoimmune activity increased due to
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Rheumatoid factor, anti-cyclic citrullinated peptide antibodies, and free light chains
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Systemic inflammation
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Elevated erythrocyte sedimentation rate, C-reactive protein
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Elevated B-cell survival factors: B-cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand)
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Increased B cells infected by Epstein-Barr virus (EBV) in circulation
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T-cell immune dysregulation in RA could lead to loss of tolerance
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T cells have marked contraction in diversity and premature telomere shortening
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Leads to permissive conditions for EBV(+) B-cell proliferation
Epstein-Barr Virus and Lymphomagenesis in Autoimmune Disease
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Virus is often present in lymphomas arising in patients with immune dysregulation
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Virus transforms primary B cells in vitro
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EBV(+) B-cell proliferation could be due to
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Immunosenescence in autoimmune disease
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MTX activated lytic EBV infection in host cells
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However, EBV can account for only fraction of increased risk
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MTX withdrawal can lead to spontaneous regression of EBV(+) diffuse large B-cell lymphoma (DLBCL)
Lymphomas in RA Patients: General Considerations
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RA is a multisystemic disease with increased risk of lymphoma
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Risk correlates with cumulative inflammatory activity
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Risk may be reduced with aggressive treatment by decreasing cumulative inflammation
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DLBCL is most common type of lymphoma
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Risk of DLBCL increased 100x from 1st to 3rd tertile of cumulative inflammation
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Long duration of RA before diagnosis of lymphoma; mean: 20 years (range: 4-50 years)
RA Patients Treated with Methotrexate
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Methotrexate is a potent immunosuppressive agent
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Activates lytic EBV infection in host cells
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Appears to cause IA-LPD in at least some patients in whom drug cessation leads to regression
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Regression is more common in EBV(+) IA-LPDs
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Complete or partial remission usually occurs within 4 weeks of cessation; remission sustained
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However, no increase in risk of lymphoma attributable to MTX demonstrated in large, population-based studies
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Risk associated with MTX therapy may appear falsely elevated due to selection bias
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Patients on immunomodulating therapy are more likely to have active disease
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Types of lymphomas described in patients treated with MTX
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DLBCL (˜ 50% of cases)
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Classical Hodgkin lymphoma (CHL) (20% of cases)
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Polymorphic/lymphoplasmacytic LPD (15% of cases)
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Follicular lymphoma (˜ 10% of cases)
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Peripheral T-cell lymphoma (rare)
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Risk of DLBCL correlates with prolonged duration of RA, therapy, and dose of MTX
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Duration of RA: Median 96 months
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Duration of MTX treatment: Median 56 months
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Cumulative MTX dose: Median ˜ 900 mg
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RA Patients Treated with Azathioprine
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Risk of lymphoma increased
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Lower risk than patients treated with MTX
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RA Patients Treated with TNF-α Antagonists
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Drugs include
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Infliximab, Adalimumab, Etanercept
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Current data indicate that treatment up to 4 years does not increase risk
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DLBCL and CHL have been reported
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Risk of lymphoma is difficult to estimate because
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TNF-α antagonists are administered to RA patients with most severe disease
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Underlying risk for lymphoma is very high in these patients
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These drugs are often combined with MTX or used in patients who previously received MTX
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Polymorphous LPDs that do not meet criteria for lymphoma can regress with drug cessation
RA Patients Treated with Other Drugs
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Risk of lymphoma does not appear to be increased in patients treated with intramuscular gold or sulfasalazine
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Risk decreased with oral steroids (odds ratio of 0.6); and intraarticular steroids
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Risk of lymphoma not yet clear for rituximab, Abatacept, Anakinra
Crohn Disease and Lymphoma
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Risk of LPD in inflammatory bowel disease increased
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˜ 2x increase independent of therapy
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DLBCL (most common); T-cell lymphomas, CHL reported
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Risk increased further by therapy with azathioprine and 6-mercaptopurine (6-MP)
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DLBCL, MALT lymphoma, CHL, and plasmacytoma
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˜ 40% of these are EBV(+)
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Risk with infliximab
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Incidence of LPDs in patients receiving infliximab for Crohn disease is 0.2-1.4%
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Small subset of cases have regressed following drug cessation
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T-cell lymphomas have been reported
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HSTCL (n=8), Sézary syndrome (n=2)
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Systemic anaplastic large cell lymphoma (n=1), cutaneous CD30(+) T-cell lymphoma (n=1)
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Infliximab may predispose to or cause lymphomagenesis due to
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Impaired T-cell apoptosis leading to decreased activated T cells in peripheral blood
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Impaired T-cell immune surveillance
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Crohn disease and HSTCL
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100% of patients were treated with azathioprine or 6-MP in past
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4-year gap between thiopurine therapy and development of HSTCL
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˜ 80% of patients had prior treatment with infliximab
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Interval between 1st dose and development of HSTCL: Median 33 months
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No reported cases of HSTCL in patients treated only with TNF-α inhibitor
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Causal role of infliximab remains unproven
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CLINICAL ISSUES
Epidemiology
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Incidence
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Not well characterized
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Overall risk of LPDs increased 2x in RA
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Severe disease activity associated with higher risk
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Concurrent treatment with ≥ 2 immunomodulator agents confounds risk assessment for specific drug
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Age
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DLBCL
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Median: 62 years
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HSTCL in Crohn disease
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Median at diagnosis: 22 years (range: 12-40 years)
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Gender
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Sex ratio related to underlying disease in most instances
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HSTCL in Crohn disease: ˜ 90% of patients are male
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Site
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Methotrexate-associated LPD
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˜ 50% are extranodal
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Gastrointestinal (GI) tract, liver, spleen, lung, kidney
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Skin, soft tissue, thyroid gland, bone marrow
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Classical Hodgkin lymphoma
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Usually involves lymph nodes
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HSTCL
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