Population-based study: Association of secondary primary malignancies and DLBCL stage at diagnosis

Since the advent of rituximab, survival rates of patients with diffuse large B-cell lymphoma (DLBCL) have improved, but secondary primary malignancies (SPMs) have emerged as an important challenge. The effect of DLBCL stage on SPM risk has not yet been specifically studied. Therefore, Ajay Major from the University of Colorado School of Medicine, Aurora, CO, US, and colleagues designed a study to evaluate whether DLBCL stage at diagnosis is associated with specific subtypes of SPM and whether stage at diagnosis affects the development of SPM subtypes.¹

Study design and patients

• Data on 26,038 patients aged ≥ 18 years diagnosed with first primary DLBCL between 1973–2010 were taken from the Surveillance, Epidemiology, and End Results (SEER) database
• Stage at diagnosis of first primary DLBCL was categorized into:
  • Early stage (ES; n= 14,274)) for disease stage I and II, or
  • Advanced stage (AS; n= 11,314)) for disease stage III and IV
  • Patients with unknown stage information were excluded
• SPM was defined as a second malignancy occurring at least 6 months after first primary DLBCL
• The treatment effect of rituximab was taken into consideration. An indicator variable identified patients who were diagnosed in the pre-rituximab versus post-rituximab era. The year 2001 was used to mark the start of the rituximab era
  • In total, 14,312 patients (ES cohort, n= 8399; AS cohort, n= 5913) were diagnosed in the pre-rituximab era, and 11,726 (ES cohort, n= 6325, AS cohort, n= 5401) were diagnosed in the post-rituximab era
• A Fine-Gray hazards model was used to assess differences in overall and location-specific SPM incidence by stage and time since diagnosis in 5-year intervals. Overall survival was compared using the log-rank test. Differences in survival were assed using a Cox proportional hazards model
• The median age of patients at diagnosis was 63 years in both cohorts, with a slightly higher incidence of males (53.3% ES cohort; 55.4% AS cohort)

Incidence of SPM

• Overall, 13.0% of the patients developed an SPM (Table 1)
• The most common SPM subtypes were hematologic (leukemia and lymphoma), male genital, pulmonary, colorectal, breast, urinary, and skin
• The median time to SPM diagnosis was 62 months (interquartile range [IQR], 25–120) for the entire cohort, and 65 months (IQR, 26–126) and 59 months (IQR, 22–112) for the ES and AS cohorts, respectively
• Median follow-up was 13.3 years (95% CI, 13.1–13.4), with a median follow-up that was slightly longer for the ES cohort than for the AS cohort at 13.9 years (95% CI, 13.7–14.1) and 12.3 years (95% CI, 12.0–12.5), respectively
• Patients in the ES cohort had a higher incidence of SPM than those in the AS cohort (14.0% vs6%, respectively)
• The 30-year cumulative incidence of SPM was 21.26% in the ES cohort and 17.46% in the AS cohort (p= 0.135)
• There were 51.2% of patients in the ES cohort and 20.1% of the AS cohort who had extranodal disease
  • Patients with extranodal disease at diagnosis had a significantly higher risk of developing SPM (hazard ratio [HR]= 1.15; 95% CI, 1.01–1.32; p= 0.018) that was not associated with disease stage

Table 1. Incidence of secondary primary malignancies (SPMs) and their site location

 

ES, (%)
n= 14,724

AS, (%)
n= 11,314

p

SPM

No

Yes

 

12,661 (86.0)

2063 (14.0)

 

9999 (88.4)

1315 (11.6)

<0.001

SPM site location

None

CNS

Head and neck

Lymph nodes

Foregut and midgut

Colorectal

Hepatobiliary

Pancreas

Pulmonary

Thyroid and thymus

Mediastinum

Skeletal

Skin

Breast

Female genital

Urinary

Male genital

Soft tissue

Hematologic

Unknown

 

12,661 (86.0)

39 (0.3)

85 (0.6)

85 (0.6)

80 (0.5)

232 (1.6)

39 (0.3)

39 (0.3)

253 (1.7)

39 (0.3)

1 (0.0)

7 (0.0)

163 (1.1)

236 (1.6)

80 (0.5)

184 (1.2)

297 (2.0)

17 (0.1)

151 (1.0)

36 (0.2)

9999 (88.4)

27 (0.2)

65 (0.6)

81 (0.7)

35 (0.3)

117 (1.0)

31 (0.3)

30 (0.3)

164 (1.4)

23 (0.2)

0 (0.0)

5 (0.0)

115 (1.0)

108 (1.0)

63 (0.6)

115 (1.0)

157 (1.4)

11 (0.1)

136 (1.2)

32 (0.3)

<0.001

CNS, central nervous system

 

Risk factors for SPM development: aggregate analysis, 1973–2010

• The risk of developing an SPM was 12% lower for the AS cohort compared with the ES cohort, but was not statistically significant after accounting for death (p= 0.135)
• A significantly higher risk of SPM development was observed for white race, male gender, advancing age, extranodal disease, and diagnosis in the post-rituximab era for all SPM locations
• Radiation therapy was not associated with SPM risk
• Diagnosis in the post-rituximab era was associated with a significantly increased risk of lymph node (HR= 2.44), thymus and thyroid (HR= 2.99), and hematologic (HR= 1.99) SPMs

Risk factors for SPM development: exploratory 5-year interval analysis

• An exploratory analysis evaluated risk factors for SPM development over 5-year intervals after diagnosis of DLBCL for all SPM locations in aggregate, as well as for individual SPM sites
• The following associations were identified:
  • Patients with ES disease were more likely to develop SPM within 0–5 years after diagnosis
  • There was no difference in SPM risk by disease stage at 5–10 years after diagnosis
  • Patients with AS disease were more likely to develop SPM within 10–15 years after diagnosis
  • There was no difference in SPM risk by disease stage at > 15 years after diagnosis
  • Patients in the ES cohort were more likely to develop colorectal, pancreas, breast, and male genital SPM at 0–5 years after diagnosis
  • Patients in the AS cohort were more likely to develop hematologic SPMs at 5–15 years after diagnosis
  • Patients with extranodal disease were more likely to develop SPMs in the 0–5-year period, specifically, foregut and midgut, colorectal, thyroid and thymus, and male genital site SPMs
  • Patients diagnosed in the post-rituximab era were more likely to develop SPM within 0–5 years from diagnosis but less likely to develop SPM at 5–10- or 10–15-year intervals
  • Patients diagnosed in the post-rituximab era were significantly more likely to develop lymph node, colorectal, hepatobiliary, pulmonary, thyroid and thymus, skin, urinary, and hematologic SPMs within 0-5 years from diagnosis

Survival and Cause of Death

• The interaction of SPM status, stage at diagnosis, and diagnosis in the pre-rituximab versus post-rituximab era was assessed for an impact on survival and found to be significant (p< 0.0001)
• SPMs significantly increased the risk of death regardless of stage at diagnosis or rituximab era, with the greatest risk of death seen in patients who had ES disease with SPMs in the post-rituximab era (HR= 3.36; 95% CI, 3.02–3.75)
  • However, diagnosis in the post-rituximab area was associated with overall improved survival compared with diagnosis in the pre-rituximab era despite increased risk of specific SPMs

Conclusions

• The risk of developing SPM in patients diagnosed with DLBCL is not the same for all patients and changes over time based on several risk factors, most importantly stage at diagnosis and time since diagnosis
• Patients with ES disease were more likely to develop SPM 0–5 years after diagnosis, and those with AS disease were more likely to develop SPM 10–15 years after diagnosis
• The development of SPM increased the risk of death regardless of DLBCL stage at diagnosis
• The study adds to the body of evidence that early- and late-stage DLBCL have distinct biology
• The authors commented that the results of this study warrant consideration of tailored site-specific and time-specific surveillance for patients with DLBCL according to stage and time interval since diagnosis