The persistent immune dysregulation in survivors of DLBCL

The introduction of rituximab and subsequent novel therapies significantly improved clinical outcomes for patients with diffuse large B-cell lymphoma (DLBCL).^1,2 However studies have shown that the surviving patients suffer from a number of health problems, such as cardiac disease, neuropathy, secondary malignancies, and decreased bone density.^3–5 Although DLBCL is a cancer of immune cells, often treated with regimens including immunomodulatory drugs, the impact of the anti-lymphoma treatment and the disease itself on the immune system has not been established.

Tanaya Shree of the Division of Oncology, Stanford University, US, and colleagues published the results from their retrospective study in the Journal of Clinical Oncology. The study investigated immune health in survivors of DLBCL up to 10 years after cancer diagnosis and compared the data with other cancer survivors.⁶

Methods

The analysis included adult patients in the California Cancer Registry (CCR) database, diagnosed with DLBCL, breast cancer (BC), prostate cancer, head and neck cancer, and melanoma, who survived ≥1 year from diagnosis.

Primary analyses used 41 immune-related condition diagnoses that were present at a rate of ≥5 events per 10,000 patients in the DLBCL cohort, as well as dermatomyositis/polymyositis and autoimmune hepatitis. A secondary analysis included 595 immune-related International Classification of Diseases 9th revision (ICD-9) codes grouped into 18 diagnostic categories.

Key findings

Characteristics of survivor cohorts

The study population included 21,690 survivors of DLBCL and comparator cohorts of 337,591 survivors of female BC, 325,533 survivors of prostate cancer, 44,245 survivors of head and neck cancer, and 73,196 survivors of melanoma.

The cohorts, in general, had similar characteristics, except for more advanced-stage disease at diagnosis in survivors with DLBCL, a higher proportion of males in the head and neck cancer survivors, and a higher proportion of non-Hispanic white race/ethnicity in the melanoma cohort. (Table 1)

Table 1. Selected characteristics of 1-Year Survivors of DLBCL, Female Breast, Prostate, Melanoma, and Head and Neck Cancers, California, 1991-2012

 

Risk of immune-related conditions of interest in cancer survivors

The incidence of several immune-related conditions was higher among survivors of DLBCL compared to other types of cancer.

DLBCL vs BC

Female survivors of DLBCL had significantly increased incidence rates for 30/43 conditions compared to female survivors of BC, including:

• Humoral deficiency (incidence rate ratio [IRR], 17.6; 95% confidence interval [CI], 12.4–24.9)
• Autoimmune hemolytic anemia (IRR, 12.0; 95% CI, 8.4–17.1)
• Fungal pneumonia (IRR, 7.4; 95% CI, 5.1–10.9)
• Sicca syndrome (IRR, 4.3; 95% CI, 3.1–5.9)
• Viral pneumonia (IRR, 3.9; 95% CI, 2.7–5.7)
• Meningitis (IRR, 3.8; 95% CI, 2.2–6.5)
• Systemic lupus erythematosus (IRR, 2.2; 95% CI, 1.5–3.1)

However, women in the BC cohort were more frequently diagnosed with cervicitis/endocervicitis (IRR, 0.41; 95% CI, 0.27–0.61)

 DLBCL vs prostate cancer

Male survivors of DLBCL compared to survivors of prostate cancer had significantly increased incidence rates  of 28/43 conditions, including:

• Humoral deficiency (IRR, 17.4; 95% CI, 12.6–24.1)
• Autoimmune hemolytic anemia (IRR, 11.6; 95% CI, 7.6–17.8)
• Fungal pneumonia (IRR, 10.8; 95% CI, 7.7–15.2)
• Viral pneumonia (IRR, 6.4; 95% CI, 4.6–9.0)
• Sicca syndrome (IRR, 5.9; 95% CI, 3.1–11.1)
• Meningitis (IRR, 5.3; 95% CI, 3.3–8.5)

DLBCL vs head and neck carcinoma

Survivors of DLBCL compared to survivors of prostate cancer had significantly increased rates of 15/43 conditions, including:

• Humoral deficiency (IRR, 11.5; 95% CI, 6.9–19.1)
• Autoimmune hemolytic anemia (IRR, 7.7; 95% CI, 4.4–13.5)
• Viral pneumonia (IRR, 4.1; 95% CI, 2.7–6.3)
• Fungal pneumonia (IRR, 3.9; 95% CI, 2.7–5.7)
• Meningitis (IRR, 3.1; 95% CI, 1.8–5.2)

The incidence of bacterial pneumonia and skin and fascial infections was higher in survivors of head and neck cancer compared with survivors of DLBCL (IRR, 0.49; 95% CI, 0.45–0.54; and IRR, 0.77; 95% CI, 0.72­–0.83, respectively).

DLBCL vs melanoma

Survivors of DLBCL compared to survivors of melanoma had a significantly higher incidence of 28/43 conditions, including

• Humoral deficiency (IRR, 13.2; 95% CI, 9.0­–19.2)
• Autoimmune hemolytic anemia (IRR, 9.1; 95% CI, 5.8­–14.3)
• Fungal pneumonia (IRR, 8.5; 95% CI, 5.7­–12.6)
• Viral pneumonia (IRR, 6.6; 95% CI, 4.4­–9.9)
• Sicca syndrome (IRR, 5.3; 95% CI, 3.4­–8.1)

 Impact of treatment and disease stage on the risk of immune-related conditions of interest

The increased risk was independent of the relapsed or refractory status and prior treatment with chemotherapy or stem-cell transplantation. However, survivors treated after the introduction of rituximab had higher incidence of humoral deficiency (16.8–20.8) compared with those treated in the pre-rituximab period (5.5–10.9).

Analysis of cumulative incidence in survivors 1–10 years after cancer diagnosis revealed that survivors of DLBCL had higher accumulation of the following diagnoses than the other cohorts of interest:

• Humoral deficiency
• Sicca syndrome
• Autoimmune hemolytic anemia
• Immune thrombocytopenia
• Infections, including viral and fungal pneumonia

Head and neck cancer survivors accumulated the highest incidence of bacterial pneumonia, followed by survivors of DLBCL, compared to other cohorts. The results of the estimated IRRs for 5–10 years after the cancer diagnosis were similar, but on average 22% lower than those from the analysis for years 1–10.

Risk of immune-related conditions of interest in survivors of DBCL vs Hodgkin lymphoma (HL)

Compared with other cancer cohorts, there were fewer differences in the incidence of the immune-related conditions between survivors of DLBCL and HL. The incidence for 10 conditions differed in the two hematological malignancies, with nine being more common among the DLBCL cohort (three significantly, p ≤ 0.0002).

Analysis of all immune-related risks among survivors of DLBCL

Analysis of all 595 immune-related diagnosis codes revealed that

• DLBCL survival was associated with a higher incidence of

• • Specific immune deficiencies (IRRs, 7.0–13.3)
  • Hematologic autoimmune conditions (IRRs, 1.9–3.1)
  • Gastrointestinal, renal, and hepatic conditions (IRRs, 1.4–2.3)
  • Diffuse autoimmune diseases (IRRs, 1.2–1.6)

• Head and neck cancer survival was associated with increased incidence of

• • Skin and bone infections (IRR, 0.76; 95% CI, 0.70–0.82)
  • Respiratory infections (IRR, 0.86; 95% CI, 0.81–0.91)
  • Oral infections (IRR, 0.10; 95% CI, 0.06–0.17)

Conclusion

This study demonstrated a persistent immune dysregulation in survivors of DLBCL, who experienced an increased risk for immune deficiencies, autoimmune diseases, and infections. This may be caused by lymphoma or the treatment regimen patients undergo during the course of the disease. The diminished immune health among DLBCL survivors may lead to additional morbidity and mortality. The authors conclude that a better understanding of these risks is important and could improve the long-term care of those patients.