Second Primaries Different in Early- vs
Late-Stage DLBCL

Pam Harrison

October 14, 2019

There is now more evidence that early- and late-stage diffuse large B-cell lymphoma (DLBCL) are two different biological entities.

Patients with DLBCL who are diagnosed with early stage (ES) disease had an increased risk to develop a secondary primary malignancy (SPM) — especially solid tumors — in the first 5 years after their diagnosis, compared with patients who have advanced-stage (AS) disease, a large population–based study indicates.

On the other hand, patients with AS disease are more likely to develop a secondary primary malignancy 5 to 15 years after their diagnosis (compared to ES patients), and in this case, the secondary malignancies are primarily hematologic.  

The new study on secondary malignancies was performed after a SWOG study showed that patients with early stage DLBCL continued to experience a higher risk of relapse even beyond the 5-year mark, said Manali Kamdar, MD, assistant professor of hematology at the University of Colorado School of Medicine in Aurora, one of the authors of the study.

"We hypothesized that if the genetic milieu of early stage DLBCL is different than that of late-stage disease, then the incidence and timing and the temporal association of secondary primary malignancies would also be different," Kamdar told Medscape Medical News.

"Our current study adds to the body of literature that ES DLBCL may have a distinct biology compared with AS DLBCL," investigators add.

The study was published online October 8 in the journal Cancer.

SEER Database

The Surveillance, Epidemiology and End Results (SEER) database was used to identify 26,038 adults who were diagnosed with primary DLBCL between 1973 and 2010.

"Stage at diagnosis of first primary DLBCL was categorized into ES for stage I and II disease or AS for stage III and IV disease," the authors write. DLBCL, the most common type of lymphoma, accounts for approximately 30% of cases of non-Hodgkin's lymphoma.

The median age at diagnosis was 63 years. Some 14,312 patients were diagnosed with DLBCL in the pre-rituximab era whereas 11,726 patients were diagnosed in the post-rituximab era.

As investigators note, survival has greatly improved since the introduction of rituximab for the treatment of DLBCL, with cure a potential goal for most patients with ES disease and for about half of those who present with AS disease.

"Overall, 13.0% of the study population developed an SPM," investigators report.

However, more patients in the ES cohort developed a secondary primary malignancy at 14% than those in the AS cohort at 11.6%, they add.

Patients who had extranodal disease at the time of their DLBCL diagnosis had a 15% higher risk of developing a secondary primary malignancy than those without extranodal disease, and this risk was independent of disease stage, researchers point out.

Risk Factors for SPM

Investigators also evaluated risk factors for the development of a secondary primary malignancy over 5-year intervals for all disease sites as well as for individual disease sites.

Five to 10 years after their diagnosis, patients diagnosed with ES DLBCL were not more likely to develop a secondary primary malignancy, as researchers point out.

Similarly, 15 years after their diagnosis, patients with AS DLBCL were not at greater risk to develop a secondary primary malignancy.

However, "we found that patients in the ES cohort were more likely to develop colorectal, pancreas, breast, and male genital SPM in the period from 0 to 5 years after diagnosis," investigators write. Typically, the male genital malignancy developed as a secondary primary was prostate cancer, they explain.

In contrast, patients with advanced disease were more prone to develop a secondary primary hematologic malignancy 5 to 15 years after being diagnosed with DLBCL, they add.

The most common types of hematologic secondary primary malignancies were acute myeloid leukemia at 27%; myelodysplastic syndrome at 21%; plasma cell myeloma at 10%; therapy-related myeloid neoplasm at 9%, and chronic lymphocytic leukemia/small lymphocytic leukemia at 7%.

Perhaps not surprisingly, the development of a secondary primary malignancy significantly increased the risk of death, regardless of the stage at which patients were diagnosed or whether or not they had received treatment with rituximab.

Furthermore, the risk of death was over threefold higher among patients who were diagnosed with early stage disease who had received treatment with rituximab and who then went on to develop a second primary malignancy at a hazard ratio (HR) of 3.36, researchers point out.

"I don't think we are at the point where our findings should influence clinical practice, but if our early stage patients are due for surveillance screening with colonoscopy, for example, then this study underscores the importance of getting surveillance for such patients," Kamdar said.

"So I would say that this study certainly puts more emphasis on age-related surveillance for subsequent cancers in early stage DLBCL patients and it's the first step toward designing a prospective trial done in a controlled setting looking at the same question," she added.

Kamdar reports receiving personal fees from Seattle Genetics, Celgene, Pharmacyclics, and AstraZeneca.

Cancer. Published online October 8, 2019. Abstract

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