Immunomodulating Agent-associated Lymphoproliferative Disorders

Tariq Muzzafar, MBBS

Key Facts

Etiology/Pathogenesis

Risk factors for IA-LPDs
- Type of immunosuppressive drug
- Duration of drug therapy
- Underlying disease type and disease activity
- Patient genetic background
EBV plays role in subset of cases

Clinical Issues

Presentation and therapy similar to corresponding LPDs in immunocompetent patients
Methotrexate-associated LPD
- Partial regression after drug withdrawal in subset of cases, especially if EBV(+)
TNF-α inhibitors
- Regression after drug withdrawal is uncommon
HSTCL in Crohn disease
- Fatal in most patients

Microscopic Pathology

Many lymphoma types described in patients on immunomodulator therapy
Analogous to other immunodeficiency states; most common are
- Diffuse large B-cell lymphoma
- Classical Hodgkin lymphoma; Hodgkin-like LPD
- Polymorphic/lymphoplasmacytic LPD
- Hepatosplenic T-cell lymphoma

Ancillary Tests

Diagnostic Checklist

Lymph node from a patient treated with methotrexate (MTX) for rheumatoid arthritis shows diffuse large B-cell lymphoma. There are many centroblasts

and mitotic figures

Skin biopsy specimen from a patient treated with MTX for dermatomyositis shows a Hodgkin-like LPD. The HRS cells

were CD15(+), CD20(+), and CD30(+) (not shown).

TERMINOLOGY

Abbreviations

Definitions

LPDs in patients treated with immunosuppressive drugs, usually for autoimmune diseases
- LPDs arising in setting of transplantation are excluded

ETIOLOGY/PATHOGENESIS

Risk Factors for IA-LPD

Type of immunosuppressive drug
- Methotrexate (MTX), tumor necrosis factor (TNF)-α antagonists, etc.
Duration of drug therapy
Underlying disease type and disease activity
- Rheumatoid arthritis (RA) appears to have highest risk
Patient genetic background
Difficult to tease out relative contributions of these factors
- Risk factors point to potential pathogenesis

Immunosenescence and Lymphomagenesis in RA

RA patients with lymphoma have mean age of 70 years (range 32-91)
- Increased age is correlated with immunosenescence
B-cell immune dysregulation in RA could drive B cell expansion
- B-cell autoimmune activity increased due to
  - Rheumatoid factor, anti-cyclic citrullinated peptide antibodies, and free light chains
- Systemic inflammation
  - Elevated erythrocyte sedimentation rate, C-reactive protein
Elevated B-cell survival factors: B-cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand)
Increased B cells infected by Epstein-Barr virus (EBV) in circulation
T-cell immune dysregulation in RA could lead to loss of tolerance
- T cells have marked contraction in diversity and premature telomere shortening
Leads to permissive conditions for EBV(+) B-cell proliferation

Epstein-Barr Virus and Lymphomagenesis in Autoimmune Disease

Virus is often present in lymphomas arising in patients with immune dysregulation
Virus transforms primary B cells in vitro
EBV(+) B-cell proliferation could be due to
- Immunosenescence in autoimmune disease
- MTX activated lytic EBV infection in host cells
However, EBV can account for only fraction of increased risk
MTX withdrawal can lead to spontaneous regression of EBV(+) diffuse large B-cell lymphoma (DLBCL)

Lymphomas in RA Patients: General Considerations

RA is a multisystemic disease with increased risk of lymphoma
- Risk correlates with cumulative inflammatory activity
- Risk may be reduced with aggressive treatment by decreasing cumulative inflammation
- DLBCL is most common type of lymphoma
  - Risk of DLBCL increased 100x from 1st to 3rd tertile of cumulative inflammation
Long duration of RA before diagnosis of lymphoma; mean: 20 years (range: 4-50 years)

RA Patients Treated with Methotrexate

Methotrexate is a potent immunosuppressive agent
- Activates lytic EBV infection in host cells
- Appears to cause IA-LPD in at least some patients in whom drug cessation leads to regression
  - Regression is more common in EBV(+) IA-LPDs
  - Complete or partial remission usually occurs within 4 weeks of cessation; remission sustained
However, no increase in risk of lymphoma attributable to MTX demonstrated in large, population-based studies
Risk associated with MTX therapy may appear falsely elevated due to selection bias
- Patients on immunomodulating therapy are more likely to have active disease
Types of lymphomas described in patients treated with MTX
- DLBCL (˜ 50% of cases)
- Classical Hodgkin lymphoma (CHL) (20% of cases)
- Polymorphic/lymphoplasmacytic LPD (15% of cases)
- Follicular lymphoma (˜ 10% of cases)
- Peripheral T-cell lymphoma (rare)
Risk of DLBCL correlates with prolonged duration of RA, therapy, and dose of MTX
- Duration of RA: Median 96 months
- Duration of MTX treatment: Median 56 months
- Cumulative MTX dose: Median ˜ 900 mg

RA Patients Treated with Azathioprine

RA Patients Treated with TNF-α Antagonists

Drugs include
- Infliximab, Adalimumab, Etanercept
Current data indicate that treatment up to 4 years does not increase risk
DLBCL and CHL have been reported
Risk of lymphoma is difficult to estimate because
- TNF-α antagonists are administered to RA patients with most severe disease
- Underlying risk for lymphoma is very high in these patients
- These drugs are often combined with MTX or used in patients who previously received MTX
Polymorphous LPDs that do not meet criteria for lymphoma can regress with drug cessation

RA Patients Treated with Other Drugs

Risk of lymphoma does not appear to be increased in patients treated with intramuscular gold or sulfasalazine
Risk decreased with oral steroids (odds ratio of 0.6); and intraarticular steroids
Risk of lymphoma not yet clear for rituximab, Abatacept, Anakinra

Crohn Disease and Lymphoma

Risk of LPD in inflammatory bowel disease increased
- ˜ 2x increase independent of therapy
- DLBCL (most common); T-cell lymphomas, CHL reported
Risk increased further by therapy with azathioprine and 6-mercaptopurine (6-MP)
- DLBCL, MALT lymphoma, CHL, and plasmacytoma
- ˜ 40% of these are EBV(+)
Risk with infliximab
- Incidence of LPDs in patients receiving infliximab for Crohn disease is 0.2-1.4%
  - Small subset of cases have regressed following drug cessation
- T-cell lymphomas have been reported
  - HSTCL (n=8), Sézary syndrome (n=2)
  - Systemic anaplastic large cell lymphoma (n=1), cutaneous CD30(+) T-cell lymphoma (n=1)
- Infliximab may predispose to or cause lymphomagenesis due to
  - Impaired T-cell apoptosis leading to decreased activated T cells in peripheral blood
  - Impaired T-cell immune surveillance
Crohn disease and HSTCL
- 100% of patients were treated with azathioprine or 6-MP in past
  - 4-year gap between thiopurine therapy and development of HSTCL
- ˜ 80% of patients had prior treatment with infliximab
  - Interval between 1st dose and development of HSTCL: Median 33 months
- No reported cases of HSTCL in patients treated only with TNF-α inhibitor
- Causal role of infliximab remains unproven

CLINICAL ISSUES

Epidemiology

Incidence
- Not well characterized
  - Overall risk of LPDs increased 2x in RA
  - Severe disease activity associated with higher risk
  - Concurrent treatment with ≥ 2 immunomodulator agents confounds risk assessment for specific drug
Age
- DLBCL
  - Median: 62 years
- HSTCL in Crohn disease
  - Median at diagnosis: 22 years (range: 12-40 years)
Gender
- Sex ratio related to underlying disease in most instances
- HSTCL in Crohn disease: ˜ 90% of patients are male