Researchers have for the first time shown that older patients with certain types of non-Hodgkin lymphoma (NHL) treated with fludarabine-containing chemotherapy (with or without rituximab), or those diagnosed with T-cell–activating autoimmune conditions, have an increased risk of developing cutaneous melanoma. The findings from this large-scale, population-based study, now online ahead of print in the Journal of Clinical Oncology (doi: 10.1200/JCO.2014.60.2094) thus identify high-risk survivors of NHL who would benefit most from regular full skin examinations to maximize opportunities for early detection of cutaneous melanoma.
The study's lead author, Clara J.K. Lam, PhD, of the National Cancer Institute's Radiation Epidemiology Branch, noted in an interview that although treatment advances have substantially improved the prognosis for NHL patients, secondary malignancies remain an important cause of morbidity and mortality among the approximately 700,000 survivors of NHL in the United States. Compared with the general population, survivors of NHL have an increased risk of developing melanoma, with particularly elevated risks among survivors of more indolent NHLs, specifically the type known as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
“We know that survivors of NHL have an increased risk of developing melanoma, but the reasons were not well understood. Our study linked two large databases—Surveillance, Epidemiology, and End Results (SEER)-Medicare and Medicare claims—to identify risk factors for developing melanoma among survivors of NHL, and we found that survivors of CLL/SLL who were treated with fludarabine had an approximately two-fold increased risk of developing melanoma compared with survivors who did not receive that treatment.
“In addition, the results showed that survivors of CLL/SLL who had a history of certain autoimmune conditions also had about a two-fold increased risk of developing melanoma, compared with those who didn't have those autoimmune conditions.”
Lam and her colleagues evaluated second melanoma risk among 44,870 one-year survivors of first primary NHL who were diagnosed at age 66 to 83 from 1992 to 2009. A total of 202 second melanoma cases occurred among survivors of NHL, including 91 after CLL/SLL and 111 after other NHL subtypes.
Melanoma risk after CLL/SLL was significantly increased among patients who received infused fludarabine-containing chemotherapy with or without rituximab. Significantly elevated risks also were associated with T-cell activating autoimmune diseases diagnosed before CLL/SLL or after CLL/SLL.
In contrast, among patients with other NHL subtypes, melanoma risk was not associated with specific treatments or with T-cell/B-cell immune conditions.
“Although our data supported the role for immune dysfunction, and T-cell dysfunction in particular, in the development of melanoma after CLL/SLL, the exact mechanism remains unknown,” Lam said. “Further research will be needed to characterize the specific immune system abnormalities that impact melanoma.”
In general, most infections did not seem to be related to melanoma risks, except for urinary tract infections (in CLL/SLL patients), localized scleroderma, pneumonia, and gastrohepatic infections (all in patients with other NHLs).
The researchers noted that CLL/SLL patients experience “profound, prolonged” immune dysfunction characterized by defective B-cell and T-cell function. This contributes to an increased incidence of infections and autoimmune diseases.
Previous studies have shown an increase in the risk of second cancers, particularly skin cancers, as well as treatment-related acute myeloid leukemia and solid malignancies in fludarabine-treated patients with CLL/SLL. But this is the first study to directly compare the melanoma risks in patients treated with and without fludarabine.
More Advanced, More Aggressive
Melanomas occurring after CLL/SLL were more likely to be at least one millimeter thick compared with those occurring after other NHLs—“which is consistent with previous studies reporting these melanomas to be more advanced and more aggressive than melanomas that arise in the general population,” Lam and her colleagues wrote.
The clinical success of immunotherapy directed at T-cell checkpoints in treating metastatic melanoma shows the importance of T cells in the antitumor response in patients with melanoma, they added.
Regarding the study's limitations, the team added that there were no data on the dose and duration of chemotherapy, and information on oral chemotherapy agents—including chlorambucil or other oral alkylators—was not available for the duration of follow-up. In addition, because of the nature of the Medicare claims database, some exposures may have been misclassified. Also, patients younger than 65 at NHL diagnosis were not included, so the findings may not be generalizable to younger populations.
In summary, she said: “NHL survivors who are 65 and older, especially those treated with fludarabine and/or who have autoimmune diseases, may benefit from regular full body skin examinations to maximize opportunities for early detection of melanoma. Hematologist/oncologists and physicians involved in long-term follow-up care for these patients should be aware of the risks of second malignancies in those treated with fludarabine chemotherapy.”
‘Clearly at Increased Risk’
Asked for his perspective for this article, Jeffrey M. Weinberg, MD, Associate Clinical Professor of Dermatology at Mount Sinai School of Medicine in New York, said: “These older NHL patients are clearly at increased risk of melanoma. Oncologists can help prevent the development of melanoma in their NHL patients by arranging frequent all-body skin exams with dermatologists, and by suggesting that their patients perform self-exams monthly. Oncologists should connect with their local dermatologists to work collaboratively on this issue.”