Risk Factors for the Development of Cutaneous Melanoma after Allogeneic Hematopoietic Cell Transplantation
Authors: Herr Megan , Curtis Rochelle E. , Tucker Margaret A. , Tecca Heather R. , Engels Eric A. , Cahoon Elizabeth , Battiwalla Minoo , Buchbinder David K. , Flowers Mary E. D. , Brazauskas Ruta , Shaw Bronwen E. , Morton Lindsay M. 
Published: October 2019

Abstract
Introduction
Advances in clinical practice for allogeneic hematopoietic cell transplantation (HCT), a potentially curative treatment most frequently indicated for hematologic malignancies, have led to substantial improvements in prognosis. HCT survivors are at risk for a number of post-transplant complications, including the development of new malignancies. Although cutaneous melanoma risk is known to be increased after HCT, no previous study has comprehensively investigated risk factors in order to identify patients at highest risk for melanoma development. The purpose of this study was to identify risk factors for developing melanoma after allogeneic HCT, specifically evaluating the relationship between melanoma and conditioning regimens as well as factors associated with immunosuppression and immune dysfunction.
Methods
We conducted a nested case-control study of melanoma within a cohort of 21,590 patients receiving a first allogeneic HCT during 1985-2012, as reported to the Center for International Blood and Marrow Transplant Research. Data on patient and transplant characteristics derived from standardized reports pre-HCT, 100 days and 6 months post-HCT, and annually thereafter or until death. The cohort was restricted to non-Hispanic Caucasians because melanoma is rare among other racial/ethnic groups. Among cases with a melanoma diagnosis reported by transplant centers (N=140), 82 (59%) were confirmed by pathology report review. Four controls were matched to each case on age at HCT (±3 years), sex, primary disease, and time since HCT (without a melanoma diagnosis). Conditional logistic regression was utilized to assess risk factors associated with melanoma development after allogeneic HCT. Multivariable models were adjusted for ambient ultraviolet radiation (UVR), estimated based on residence at the time of HCT, because of the known association between UVR and melanoma. Exploratory analyses were conducted to assess melanoma risk by age and time to melanoma development.
Results
Among the 140 melanoma cases, the median age at HCT was 46 years (range, 1-73 years), 56% were male, and median time from HCT to melanoma was 4 years (range <1-24 years). Patients were most frequently transplanted for chronic myeloid leukemia (24%) followed by acute myeloid leukemia (18%), acute lymphoblastic leukemia (18%), and non-Hodgkin lymphoma (12%). Multivariable analysis showed that melanoma risk was statistically significantly increased among HCT survivors who received myeloablative conditioning regimens with total body irradiation [odds ratio (OR), 95% confidence interval (95%CI): 1.8, 1.0-3.2] or reduced intensity conditioning regimens containing melphalan (OR, 95%CI: 2.6, 1.1-6.0) or fludarabine (OR, 95%CI: 2.7, 1.0-7.3) compared with those receiving a busulfan-containing myeloablative conditioning regimen; acute graft-versus-host disease (GvHD) with stage 2+ skin involvement (OR, 95%CI: 1.9, 1.2-3.1) versus no acute GvHD; chronic GvHD without skin involvement (OR, 95%CI: 1.9, 1.0-3.6) versus no chronic GvHD; and occurrence of keratinocytic carcinoma (OR, 95%CI: 2.4, 1.2-4.8; median time from keratinocyte carcinoma to melanoma: cases=3.5 years, controls=2.8 years). In exploratory analyses of these factors by patient subgroup, melanoma risks associated with acute GvHD stage 2+ skin involvement were especially increased among individuals of younger age at HCT (age<40 years: OR, 95%CI: 3.2, 1.4-7.4) but not among those of older age at HCT. In the multivariable model, no significant associations were observed with other patient and transplant characteristics, including graft source and ex-vivo or in-vivo T-cell depletion.
Conclusion
In the largest study to date of melanoma risk factors following allogeneic HCT, we report novel associations with specific conditioning regimens, occurrence of acute and chronic GvHD, and occurrence of keratinocyte carcinoma. Our results emphasize the importance of adherence to current surveillance guidelines for HCT recipients, specifically routine skin examination, heightened skin cancer awareness, and photoprotection recommendations, particularly for those survivors at highest risk.

Disclosures
No relevant conflicts of interest to declare.